Fell Foal Syndrome - Research Progress
Report
September 2000
Notes from a talk
to Fell Pony Society members in the UK compiled by Sue Millard (UK)
1st September
2000 at Preston Patrick Memorial Hall (UK)
by Dr Gareth Thomas*
Introduction
and Supplemental Information (denoted by *. . . ) by Mary Jean Gould-Earley (USA)
following her discussion
of these notes with Dr. Thomas (September 2000)
Introduction
"Fell Foal Syndrome" is a devastating. lethal disease that has been seen in the UK and Germany and only in Fell Pony foals. To date there have been no documented cases in North America. The syndrome is comprised of severe anemia and impaired immunity and is invariably fatal, with the foals usually dying or being put down by 3-4 months of age. Because the syndrome has not been seen in other breeds, it is assumed to be genetic in origin – probably recessive – although to date this has not been proven. The research team at Liverpool University has been busy studying this and they are in the process of collecting blood samples from a large number of ponies in hopes of isolating a defective gene and thus developing a carrier test. This syndrome is of grave concern given the very small gene pool of the Fell, with an estimate of only 5000-6000 ponies living worldwide! Research into this matter is thus critical to the survival of the Fell. If the syndrome is proven to have a genetic cause and if a carrier test can be developed, appropriate breeding recommendations can be made by the Fell Pony Society. Assuming it is proven genetic in origin and carriers can be identified, it is likely that selective breeding (rather than elimination) of carriers would be recommended to avoid producing syndrome foals. If the worst case scenario speculations are true and we indeed have a large number of carriers in the population, elimination of these ponies from the breeding stock must be avoided. This is because any further narrowing of the already small gene pool would be devastating to the breed!
The syndrome remains somewhat of a mystery, but the researchers hope to have answers in the very near future. It is critical that breeders work together to bring the Fell pony through this crisis to survive as a breed. The research is ongoing. Below is the latest information from the researchers at Liverpool University from September, 2000. This progress report is courtesy of Sue Millard who compiled the original notes. I was able to forward these notes to Dr. Thomas for review and additional notes were added based upon my direct communication with him. Some background/supplemental information is also provided. As further progress reports become available, the information will be updated.
*Gareth Thomas,
BVM&S MRCVS, is on the Faculty at Liverpool University (UK) in the Dept. of
Veterinary Immunology. He currently works full-time on syndrome research with Dr. Stuart Carter. Note that,
according to Dr. Thomas, this talk as well as "Fell Pony 2000" reports
may be somewhat "oversimplified" for ease of understanding by
non-scientists or lay people (i.e.., Fell breeders/farmers). Furthermore, the
target audience is supposed to be "breeders
in the UK to try to generate support for the research effort".
Without breeder support there can be
no research. The information is in need of further explanation to
put it into perspective for those unfamiliar with the Fell Pony breed,
remembering that it is still based somewhat on theories particularly regarding the prevalence of a lethal recessive
gene.
Newcomers to information on this breed should clearly understand there is much more research to
be done to prove the etiology of this disease and to determine its true
incidence in the population as well as the prevalence of carriers. The
news media has been filled with grossly exaggerated stories regarding the
magnitude of this problem, citing an incidence of foal death due to the syndrome
to be as high as 60% which is simply
not true!! You should
also know that "Fell Pony 2000" is a charity to support research on the syndrome – it is not the research
team. The more breeder support that
they solicit, the speedier the research will progress so everyone’s help
is vitally important.
The syndrome
** Regarding "nothing else causes anaemia in foals this young” . Taken literally, this is an incorrect statement (intended to be an oversimplification)– there are other causes of anemia in young foals. Anemia, or low red blood cell count, has many causes, and mild anemia is common and seen with many diseases/toxicities/deficiencies, including just poor nutrition. In the UK, however, they have seen rather profound anemia which they reportedly haven’t seen to this severe degree other than in young Fell foals. In North America, at least, the same degree of anemia could have many causes, including fescue toxicity, EIA (Equine Infectious Anemia, often referred to as "Coggins" (the test used to diagnose EIA)), etc. EIA, by the way, is unheard of in the UK (i.e.., the disease doesn’t exist). Dr. Thomas added that “We can’t rule out toxins, etc. (as being the cause of the syndrome). But the incidence of disease doesn’t suggest this type of etiology” (i.e.., seeing this syndrome only in Fells). The syndrome is NOT proven to be genetic in origin but they believe it is mainly because of the isolated incidence (thus far) in Fells. The problem is not definitely proven to be genetic because to do so you would have to set up an experimental breeding program with known carriers and run it over 8 years - but who would subject their mare to that? Conversely there is no evidence of "pockets" of infection or susceptibility on individual farms or areas to suggest that the problem is infection or mineral deficiency. Studs producing syndrome foals also produce normal, totally unaffected foals and the numbers vary from year to year - sometimes 5 foals in a year, and sometimes none, are syndrome foals. Deficiencies in minerals or vitamins such as selenium or Vitamin E, whose lack depresses the immune response, have been looked at and dismissed as causes. ALL the Fell pony samples, both normal and syndrome, were deficient in selenium when compared to samples from other breeds - so this is not necessarily a "cause" but perhaps a contributory factor in certain ponies.*** ***Note: Selenium is a trace mineral known to cause problems in many animal species when there is either deficiency (from too little) or toxicity (from too much). It is found in safe quantities in many animal feed supplements worldwide. It is important to note that selenium deficiency can be lethal in foals and is associated with immune suppression. The pregnant mare must be supplemented with selenium (a practice very uncommon in the UK!!) to avoid possible irreversible immune suppression in the foal. If a foal is born with selenium deficiency, it is usually too late and treating the foal with selenium may not help. Since ALL Fell pony samples – those with syndrome and those without – were deficient in selenium, one cannot separate the effects of selenium deficiency on the immune system relative to possible genetic or “syndrome” effects. Cumbria (where most Fells are in the UK) is reportedly deficient in selenium, as are many areas of Germany and the US, etc. Dr. Thomas tells me that “there is disagreement about the best way to measure Selenium” (in animals) which may confuse the issue further. He says “Our study into Selenium is still continuing, however.” It is considered that the problem therefore is genetic**** and that the carrier status is at saturation, i.e. there will be no increase in the number of ponies carrying the gene. Statistically it is probable that two-thirds of the population is of carrier status and 10-20% of foals per year will be syndrome foals, but not more than this. (IF a treatment is found which enables homozygous syndrome foals to survive and breed, the risk of breeding a syndrome foal goes up from 1:4 to 1:2. Therefore, treatment may be good news for an individual animal, but bad news for the breed if it survives to breed in its turn. So far no affected foals are known to have survived, so health status in later life is unknown. 2 foals said to have been successfully treated by Paul May are, possibly, not syndrome foals at all. They are poor specimens, e.g. the colt has no testicles yet.) *****They are assuming that if the disease is genetic it is caused by a lethal recessive gene. What does this mean? Genes (genetic material) run in pairs and a carrier has one good and one bad gene in the pair. Since only one gene from the pair is passed on to any particular offspring (basically a crap shoot which one will be passed on), the offspring has a 50% chance of inheriting the bad gene from that parent. If the carrier is bred to another carrier, statistically there is a 25% (or 1 out of 4) chance that the foal will receive a bad gene from both parents (which is lethal). There is a 50% chance that the foal will be a carrier (but otherwise is healthy) by receiving a good gene from one parent and a bad gene from the other. Finally, there is a 25% chance that the foal will be totally normal with 2 good genes (one from each parent). Please note that carriers (if they exist) have no symptoms at all (i.e., are perfectly healthy). Thus, there will be a 75% chance (3 out of 4) of a healthy foal, remembering that some will be carriers. If a carrier is bred to a non-carrier, you will never produce a syndrome foal!! This is very important and is the basis for "selective" breeding (i.e., being careful to breed carriers only to non-carriers). You will produce more carriers this way (50% carriers, 50% non-carriers produced) but this is unavoidable since the Fell population is too small to eliminate all the carriers (if carriers exist!) Selective breeding requires a carrier test (to determine if the breeding animal carries a lethal gene) to be effective. The probable cause of the emergence of the syndrome is line breeding/inbreeding in the 1960s. Historical pedigrees (Stud Book data) are not sufficiently accurate to definitely pinpoint an original carrier animal though it is known that there is one stallion, heavily used in the 1950s (when the enclosure system was current) who appears significantly in the pedigree of every syndrome foal known so far.***** Some of this stallion’s progeny were also used in the Dales breed but not sufficiently to produce a syndrome foal there - unless stock are bred back to the same line the fault does not surface. Rumours of Dales "syndrome foals" are only rumours. Dr Thomas was careful not to say which stallion this was. He remarked that for research testing purposes the pedigree was interesting but not important. He was content to accept mares with sick foals for investigation without knowing their breeding. *****This issue seems unclear also, only because there are some stallions used back then that appear in a huge percentage of pedigrees, and like the selenium issue, there are few “controls” to compare to (i.e.., how many unaffected pedigrees does that same stallion appear in?) Dr. Thomas said “Due to major inaccuracies in the Stud Book, nothing can be proven but a bottle neck occurred around this time.” Nonetheless, please remember that inbreeding/line breeding is noted to be the “probable cause”, and even if this turns out not to be true in this case, it is something we all must avoid to prevent expression of other as yet unknown genetically recessive diseases that may be harbored in the Fell gene pool. There are other problems seen in a narrow gene pool that only get worse with further inbreeding – subfertility is one. (It is something we see all too commonly in Friesians for the same reason (narrow gene pool). ) Inbreeding is also how recessive diseases in other breeds of horses came to be, such as SCIDS (in Arabians) and HYPP (in Quarter Horses) -- by using the same horses over and over for breeding which resulted in a very narrow gene pool full of carriers. Mares and foals at Leahurst included normal and sick foals. Blood and DNA sampling was done, and genetic testing is in progress to find the "syndrome gene". 95 animals have been microchipped, which is essential for future identification. Identification by whorls is not sufficiently specific. 7 mares were at Leahurst:
Approx 300 foals are born per year so this is NOT a representative sample.****** ******Please note again that this is NOT a representative sample. What does this imply? The estimated 2/3 carrier rate is based upon the samples obtained -- with 10-15% incidence you would expect 2/3 of the population to be carriers if the disease is recessive. This is purely a statistical number based on the relatively small sample obtained. There are at least 250-300 foals registered each year, so (for example) if there were only 8/300 foals with the syndrome (as opposed to 8/85 sampled), the incidence would be 2-3% and the estimated carrier rate would then be only 10%. However, Dr. Thomas suspects the true incidence of the syndrome is as high as 10% or so because of the data obtained from the samples in addition to a number of anecdotal reports of foal deaths. Nonetheless, he also agreed that it is possible that the true incidence is lower, and it is thus possible that the carrier rate is much lower than speculated in this and the FP2000 reports (again ASSUMING a recessive mode of inheritance) because of a possible nonrepresentative sample population being studied. In any case, not all affected foals may be reported, making it impossible to determine a true incidence at this time. Cooperation of all breeders is ESSENTIAL in this research. Dr. Thomas stated “I chose the numbers for the talk based on the data we have. These may be a little high . . . The main reason for the talks was to stimulate interest in the disease and to encourage people to help our research. The same "numbers" are used in the FP 2000 literature. So what is presented is the WORST CASE SCENARIO in which there is “saturation” of carriers in the population (as high a percentage as possible), which hopefully gets all the breeders' attention! It is possible that the numbers are in fact this high, but time will tell. . . If proven to be due to a recessive fault, unfortunately right now development of a carrier test is felt to be "a long way off". Incidentally, there were 7 foals born in North America in 2000 with 0% incidence of the syndrome!! 2001 Plans
In the syndrome foals, the stem cells in bone marrow are mostly absent. It may be the bone marrow matrix which is deficient and fails to produce the stem cells; those produced are normal but too few. Last year research focused on the T cells, this year on the B cells. Useful pointers have been seen but they are not exclusive to the syndrome so a test is not yet available.******* *******The only tests being used right now to "confirm" the syndrome are bone marrow sampling and lymph node sampling. It is important for breeders to be aware of this in the event of foal illness or death -- both of these must be obtained in order to determine if the foal has or had the syndrome, otherwise the diagnosis cannot be made with certainty. Dr Thomas indicated that breeders may already be culling stallions thought to be carriers on the evidence of syndrome foals produced; "3 stallions have gone this year" - presumably meaning "put down" or possibly gelded.) Dr Thomas’ opinion is that mare owners will in effect force stallion owners to test their stock - they will not use stallions that are untested. Once a test is available it will only require all stallions to be tested to ensure that no more syndrome foals are born. (I.e., one year.) The test will only test for this syndrome and will have to be 99.99% specific. A carrier stallion should then only be bred to tested non carrier mares. The gene can eventually be bred out - this will take longer, as a mass cull of carrier animals would devastate the breed (remembering that two thirds are suspected to carry the gene).****** Testing of large numbers of mares would be prohibitive in cost to breeders and there will have to be some subsidisation if the test is going to be widely used. The equine genome has not yet been mapped but Newmarket are in the process of doing so. This will be enormously helpful in pinpointing which gene is the carrier. However, their work will not be publishable for another couple of years. *******Please again note that a mass cull of carrier animals would devastate the breed if this is indeed a recessive disease! It is frightening to think that emotions may get in the way of common sense here and stallions will be indirectly be “culled” because mare owners won’t want to breed to them even if the mare is not a carrier (or if they don’t want to have to pay to have the mare tested for carrier status). So then the remaining ponies are inbred and you develop a huge number of other problems . . . What a devastating affect this could have on the already-too-narrow gene pool! Please keep this in mind when/if this syndrome is proven genetic and also proven recessive, and certainly if a carrier test exists. . . If the disease is due to a lethal recessive gene, one must again realize that even if you breed carrier to carrier, 75% of foals will be "normal" (50% asymptomatic carriers and 25% non-carrier), while 25% of foals will have syndrome. As long as you breed carrier to non-carrier, you will never produce a syndrome foal -- thus the importance of a carrier test!
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The syndrome |
Sue Millard is a Fell owner in the UK and author of "One Fell Swoop" http://members.xoom.com/suemillard/page2.htm
Mary Jean Gould-Earley, MD is a Fell owner and breeder at Laurel Highland Farm in Pennsylvania, USA http://www.laurelhighland.com