Lethal White Syndrome

     (2) Overo Lethal White Syndrome  (3) Overo Lethal White Syndrome Update

Lethal white foals are usually produced when an overo mare is bred to an overo stallion, but can also occur with crosses with tobiano and others with overo ancestry.  Lethal white syndrome is a condition of foals born with a deadly genetic defect - one that is linked with the white pattern so coveted by breeders. Although the defect is linked to the white pattern, not all horses with white carry the gene that is responsible for the symptoms of lethal white syndrome.

This defect is the result of a mutation in the gene sequence in the overo phenotype. Research has identified the mutation as the Lys118 allele (a pair of genes position on the same site on paired chromosomes, containing specific inheritable characteristics) that is inexplicitly joined to the early formation of the lower gastrointestinal tract in the fetus.

When two white patterned horses carrying the gene (heterozygous carriers) are bred, there is a 25% chance that the foal will be conceived with a copy of the mutation from each parent, making him homozygous for the condition. Unfortunately, a foal carrying both copies will exhibit the symptoms of lethal white syndrome.

These foals are usually born totally white, although a small spot of dark color may be apparent. More importantly, these unfortunate babies arrive with an incomplete lower colon because nerve cells in the lower portion of their gastrointestinal tract do not develop. This makes it impossible to pass the first meconium.

The consequences of their genetic make-up are not fully recognized until birth. Signs of colic are often followed by death within the first twenty-four hours. There is no treatment for lethal white syndrome, and euthanasia is the only recourse. It should be noted, however, that not all white foals are lethal white foals. Clinical signs and veterinary evaluation is paramount to determining status.

Lethal white foals are usually produced when an overo mare is bred to an overo stallion, but can also occur with crosses with tobiano and others with overo ancestry. Overo is a broad category which includes frame, calico, splashed and sabino types, and is characterized by broad white pattern reaching from the abdomen up to the middle of the back. The white does not cross the back, and is often extensive on the head. The consequences of their genetic make-up are not fully recognized until birth. Signs of colic are often followed by death within the first twenty-four hours. There is no treatment for lethal white syndrome.

Studies show that frame overos, highly white calico overos, and frame blend overos have the highest incidence of producing lethal white foals. Although many believe that all overos contain the mutation, research indicates that there are a small percentage of overo-patterned horses that do not carry the gene for lethal white syndrome. This is why certain stallions and mares never throw a lethal foal. The absence of the mutated gene in some overos indicates that the white pattern, itself, may be regulated by more than one gene.

Because the gene that causes lethal white has been identified, one can now test the status of breeding horses and decrease the odds of a lethal white foal. This DNA-based diagnostic test can be run on blood and hair with follicles attached, and the information obtained can give you a better understanding of the odds.

The odds of producing a lethal white foal may cause confusion for some. Why, you ask, if breeding an overo to an overo gives you a 25% chance of a lethal white foal, don't you see statistics verifying this percentage?

There are several reasons. First of all, not all overos carry the gene - only by breeding two overos with the mutation will you have a 25% chance of a lethal white foal. Secondly, all lethal white foal deaths are most likely not reported; It's difficult to obtain statistics of lethal white births. Finally, the incidence of lethal white is a gamble.

Roll a dice six times and see how many times you actually roll a three. Statistics would say that one roll out of every six rolls would land you a three, but this does not necessarily happen. Each time you breed two horses with the defective gene, you have a one in four chance of a lethal white foal. Sometimes you're just unlucky.

A recent study involving 945 white-patterned and 55 solid-colored horses presented for DNA identification of the lethal white gene (Lys118 allele) revealed that 73% of overos and overo blends in the study had the mutation. Frame and frame blend overos had the highest incidence of occurrence with 96% positive for the lethal gene, while 100% of loud calicos (all 37 loud calicos represented in the study) contained the mutation.

White patterns with the lowest incidence of Lys118 allele included splashed white overo, sabino, minimal white calico overo, nonframe blend overo, tobiano and breeding stock solid. Breeding stock horses of the American Paint Horse lineage always have some white markings, and the incidence of the lethal white gene in this particular study ran 18% (26 horses out of 146 tested).

Without knowing the genetic make-up, the best means of improving your odds in avoiding lethal white is to cross an overo with a solid or tobiano. The incidence of the Lys118 allele is much lower in tobianos (10%, or 11 out of 109 horses tested in the study carried the gene), and those with the greatest risk have overo lineage in their ancestry.

Solid-colored (without any white) horses appear to not carry the mutation, which is directly related to white coat pattern, so one can drastically reduce the odds of conceiving a lethal white and still have a 50% chance of obtaining an overo foal by breeding an overo to a solid.

While the thought of conceiving of lethal white foal may be worrisome, the actual percentage of foals born with this condition is relatively low. With the aid of DNA testing, you can selectively breed with confidence. A beautiful colored foal is a sight to behold.

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Overo Lethal White Syndrome (OLWS) is a condition that occurs in newborn foals. The condition is genetic, and both parents carry the defective gene. Horses which carry this gene are most commonly overo white patterned horses (frame overos), but there are exceptions. The defective gene has been found in American Paint Horses, American Miniature Horses, Half-Arabians, Thoroughbreds, and cropout Quarter Horses (foals born to registered Quarter Horse parents which have too much white to qualify for registration with the American Quarter Horse Association).

OLWS foals have blue eyes and are completely or almost completely white at birth. These foals initially appear normal except for their unusual coloring. After a varying period of time, troubling signs of colic emerge due to the foal's inability to pass feces. The OLWS foal has an underdeveloped, contracted intestine caused by a failure of the embryonic cells that form nerves in the gastrointestinal system. Oddly enough, these cells also play a role in determining skin color. There is no treatment for OLWS, and surgery to bypass the intestinal damage has never been successful due to the extensive nature of this type of lesion. Veterinarians advise euthanasia for all OLWS foals because death will inevitably occur from colic caused by fatal constipation.

The birth of an OLWS foal is emotionally injurious and often financially devastating for small breeders because the syndrome is always fatal. Identifying an individual's propensity for passing on this disease is essential, and research at the University of Minnesota is making prevention a real solution. Horse breeders now can eliminate the possibility of the birth of an OLWS foal by testing their breeding stock. Using clues from genetic defect studies on lab animals and humans, this research found a mutation in OLWS foals .

Using these clues from other species, researchers at the University of Minnesota investigated the same genes in OLWS foals, and found a mutation. A test for the defective allele (each gene is made of two alleles, one inherited from each parent) was quickly developed. Testing of OLWS foals, their parents, and unrelated horses revealed that all OLWS foals had two copies of the defective gene, their parents had one, and unrelated horses had none. Simply put, if carriers are never again bred to each other, there can never be another OLWS foal born.

Horses at greatest risk of carrying the defective allele are overos, particularly of American Paint Horse and American Miniature Horse breeding. A small number of Tobiano and breeding stock horses also carry the defective gene, and a very small number of carrier horses have been detected in other breeds. These other carriers include Pinto horses, which indicates that as other breeds import overo color patterning, they also can import the lethal gene.

We recommend that horse owners concerned about the possibility of their breeding stock's carrying the defective gene contact their veterinarian about the chances and request a professional opinion about how to proceed with further testing.

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The same researchers who identified the gene mutation that causes deadly overo lethal white syndrome (OLWS) have more accurately determined the coat patterns associated with OLWS in newborn foals. The effects of OLWS are wide-reaching, as it has been found in Paints, Miniature Horses, half-Arabians, Thoroughbreds, and cropout Quarter Horses (Quarter Horse foals born with too much white to be accepted into the breed's registry).

Elizabeth M. Santschi, DVM, Dipl. ACVS, clinical associate professor at the University of Wisconsin's School of Veterinary Medicine, was a principal researcher in the University of Minnesota studies. Overo lethal white syndrome has been a frustrating problem for breeders, as the condition is always fatal. "Basically you get this all-white foal born apparently healthy, but he never passes feces and he eventually colics and dies," explains Santschi. "There's nothing you can do. As a surgeon, I always want to do something, and there's nothing I can do (for OLWS foals). The only way to avoid this condition is to not breed them."

This led to studies examining the genetics behind OLWS. The condition was associated with its namesake overo coloring in carrier parents (characterized by white coloration of the abdomen that does not cross the dorsal midline between the withers and tail). Symptoms are similar to a genetic condition (Hirschprung disease) that appears in humans and rodents, so Santschi's group targeted the same gene in the horse. In 1998, the group revealed in Mammalian Genome that a mutation of the endothelin receptor B (EDNRB) gene was associated with OLWS. Lethal white foals have two copies of the defective allele (two alleles make up a gene, one from each parent), while their healthy carrier parents have one, and non-carrier horses have none. They deduced that if one-copy horses were not bred to each other, OLWS would never occur. "The beauty of it is, you can test your horses before breeding to see if you have a carrier," says Santschi.

But not all overo horses are phenotypically the same, as there are four distinct overo subtypes (frame, calico, sabino, and splashed white). And not all overos produce affected foals, which left questions about which subtypes are affected. The latest study included 1,000 horses from farms that had never experienced OLWS, and farms that had high incidence of the syndrome. "We took photos and DNA samples to try and determine how this mutation determines coat color or white patterning," explains Santschi.

They found that in heterozygotes (horses with one normal and one defective allele in the EDNRB gene), the mutation is usually responsible for a frame overo pattern (see www.apha.com/association/PDFFiles/01geneticsguide.pdf). Since frame overos' characteristic pattern can be altered through breeding to horses with other patterns, accurate visual inspection of carriers of the defective gene can be difficult due to blending of the patterns.

It was also found that other genes control both overo and tobiano (the other main type of white patterning recognized by the American Paint Horse Association) patterning besides EDNRB. Therefore, researchers deduced that determination of EDNRB genotype by use of a DNA-based test is the only way to determine with certainty whether a white-patterned horse can produce a foal affected with OLWS.

Santschi added, "If you can't tolerate a lethal white, you should test your horses."

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