The disease has a similar etiology to Hirschsprung's disease in humans. A mutation in the middle of the Endothelin receptor type B (EDNRB) gene causes Lethal White Syndrome when homozygous. Carriers, who are heterozygous, that is, have one copy of the mutated allele, but themselves are healthy, can now be reliably identified with a DNA test. Both parents must be carriers of one copy of the LWS allele in order for an affected foal to be born.
Horses that are heterozygous for the gene that causes LWS often exhibit a spotted coat color pattern commonly known as "frame" or "frame overo." Coat color alone does not always indicate the presence of LWS, or carrier status, however. The frame pattern may be minimally expressed or masked by other spotting patterns. There also are different genetic mechanisms which produce healthy white foals and have no connection to LWS; another reason for genetic testing of potential breeding stock. Though there is no treatment or cure for LWS foals, a white foal without LWS that appears ill may have a treatable condition.
Healthy foals pass meconium, the first stool, soon after birth. Some healthy foals may require an enema to assist this process. But the meconium of LWS foals is impacted high in the intestine, and never appears, even with the use of enemas. Symptoms of colic begin to appear within the first day, and all LWS-afflicted foals die within the first few days of life. The painful and inevitable death that follows usually prompts veterinarians and owners to euthanize foals suspected of having Lethal White Syndrome.
The reason death occurs is because part of the digestive system is underdeveloped. The large intestine of the horse is a complex system where most digestion takes place, and is comprised of the cecum, the colon, and the rectum. Necropsies on Lethal White Syndrome foals reveal a pale, underdeveloped colon and intestinal obstruction (impaction). Samples of affected tissue show a lack of nerves that allow the intestine to move material through the digestive system, a condition called intestinal agangliosis.
Closer examination of the skin and hair shows both to be unpigmented, and most hair follicles are inactive and many are devoid of hair altogether. All Lethal White Syndrome foals test homozygous for a genetic abnormality.
Such regulatory genes include Endothelin receptor type B (EDNRB). A mutation in the middle of the EDNRB gene, Ile118Lys, causes Lethal White Syndrome. In this mutation, a "typo" in the DNA mistakes isoleucine for lysine. The resulting EDNRB protein is unable to fulfill its role in the development of the embryo, limiting the migration of the melanocyte and enteric neuron precursors.
In the case of LWS, a single copy of the EDNRB mutation, the heterozygous state, produces a visible trait, but with a very different outcome from the homozygous state. In genetics, when heterozygotes express a trait, but are distinguishable from homozygotes, the gene is said to be an "incomplete dominant." An example of this in a coat color gene without lethal traits is the cream gene, which produces different coat colors in a heterozygous and homozygous state. Pleiotropy complicates the distinction between dominant and recessive genes in this circumstance, but since even heterozygotes have traits distinct from non-carriers, the gene is essentially a dominant.
To produce a foal with Lethal White Syndrome, both parents must be heterozygotes or carriers of the mutated gene. Without genetic testing, some carriers are misidentified as having white markings due to another gene, while some are even classified as solids.
The presence of this gene in a variety of horse populations in North America suggests that the mutation occurred in early American history, perhaps in a Spanish-type horse.
Not all horses with the heterozygous mutation exactly fit the standard visual description. A horse with the Ile118Lys mutation on EDNRB that is not readily identified as frame-patterned is called a cryptic frame. In addition to cryptic frames, a significant proportion of horses with the frame phenotype are visually misidentified, even in clinical settings. One study found from a group of visually-inspected registered Paints, 18% of breeding stock solids and 35% of bald-faced horses were actually frames. On the other hand, over one quarter of Paints registered in the \"overo\" category were not frames, and at the same time, 10% of horses registered as tobiano were also frames. The difficulty in accurately identifying frames has contributed to the accidental breeding of Lethal White Syndrome foals.
Minimally-marked horses heterozygous for the Ile118Lys mutation are not uncommon: one DNA-tested Thoroughbred has white markings limited to a bottom-heavy blaze and two socks below the knee. A Quarter Horse mare tested positive for the gene after she and a frame Paint stallion produced a Lethal White Syndrome foal; the mare's markings were a thin blaze with a disconnected white spot in the right nostril, with no other white markings. One major study identified two Miniature horses that were completely unmarked, but were positive for the Ile118Lys gene.
There are multiple theories for this. Variability in the percentage of individuals with a specific genotype that express an associated phenotype is called penetrance, and this may simply be evidence of variable penetrance. Several research groups have suggested that other, "suppressor" genes may limit the expression of frame-pattern white spotting.
On the other end of the spectrum, some white-spotted horses are so extensively marked that the character of the frame pattern is masked. In particular, the tobiano pattern, a dominant gene, is epistatic to overo. Other white-spotting genes include splash overo or "splash," sabino, and calico. Any combination, or all, of these white-spotting genes can act together to produce horses with so much white that the presence of frame cannot be determined without a DNA test.
Ambiguous terminology has also contributed to the confusion surrounding this disease. Currently, the American Paint Horse Association (APHA) categorizes horses as tobiano, solid, "overo," and tovero. The association breaks down "overo" into three categories: Frame, Splash and Sabino. In the past, "overo" was used even more loosely, to refer to spotted animals that were "Paint, but not Tobiano." However, no fewer than four, and likely many more, genetically distinct patterns are included under the term "overo." To be categorized as "overo" by the APHA, a horse must fit a written description: white spotting does not cross the back, at least one solid-colored leg, solid tail, face markings, and irregular, scattered, or splashy white patches. To further complicate matters, various Sabino patterns also appear in some horse breeds that do not carry genetics for frame or any other spotting pattern.
Likewise, official classification of a horse as an unspotted solid is based not on genetic testing, but on a visual description. Horses carrying genetics for frame and other white-spotting patterns may be so minimally marked as to lack the registry's minimum requirements for white. This helps to account for allegedly solid horses producing spotted offspring, called cropouts.
The long-standing practice of categorizing Paint horses in this manner contributed to the incorporation of the word "overo" into some of the titles used to describe the disease, such as Overo Lethal White Foal Syndrome. However, "overo" is a term that applies to several genetically-unrelated white-spotting patterns, and only the frame pattern is indicative of the syndrome. The confusion about the nature of LWS is then furthered by statements such as "there are many overos that do not carry the lethal allele," which is technically correct, but only because the term "overo" also encompasses splash and sabino patterns as well as frame.
Because of the incomplete dominant nature of the gene, the statistic likelihood of producing a living, frame-patterned foal by crossing two frames is 1 in 2, or 50%; the same odds of producing a living, frame-patterned foal from a frame-to-non-frame breeding which carries no risk of producing a Lethal White Syndrome foal.
The terms \"piebald-lethal\" and \"spotting lethal\" apply to similar conditions in mice and rats respectively, both caused by mutations on the EDNRB gene. Only lethal in the homozygous state, the mutations are associated with white-spotted coats, deafness, and megacolon caused by intestinal agangliosis.
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