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Lethal white syndrome (LWS), also called overo lethal white syndrome (OLWS), lethal white overo (LWO), and overo lethal white foal syndrome (OLWFS), is an autosomal genetic disorder most prevalent in the American Paint Horse. Affected foals are born after the full 11-month gestation and externally appear normal, though they have all-white or nearly all-white coats and blue eyes. However, internally, these foals have a nonfunctioning colon. Within a few hours, signs of colic appear and affected foals die within a few days. Because the death is often painful, such foals often are humanely euthanized once identified. The disease is particularly devastating because foals are born seemingly healthy after being carried to full term.

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 lethal white syndrome 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.

Clinical Signs

Unlike some coat color dilution lethals, which may result in premature births, stillborn, or weak foals, foals born with lethal white syndrome appear to be fully formed and normal. The coat is entirely or almost entirely pure white with underlying unpigmented pink skin. Pigmented regions may be any color, and if present are most common around the muzzle, underside of the barrel, and the hindquarters or tail. The eyes are blue. A few lethal white foals have been shown to be deaf.

Healthy foals pass meconium, the first stool, soon after birth, though 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.

Death is caused by an underdeveloped part of the digestive system. The large intestine of the horse is a complex system where most digestion takes place, and comprises 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.

Inheritance and Expression

Genetic conditions which affect more than one physical trait-in the case of Lethal White Syndrome, both pigment cells and enteric nerve cells-are termed pleiotropic. The unusual instance of pleiotropy in LWS foals suggested early on that the syndrome was related to an important section of embryonic tissue called the neural crest. As the name suggests, the stem cells of the neural crest are precursors to nerve cells. Another cell type that descends from neural crest cells are melanocytes, pigment-producing cells found in hair follicles and skin. The migration of nerve- and melanocyte-precursors from the top of the embryo to their eventual destinations is carefully controlled by regulatory genes.

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 an identifiable trait, but with a very different outcome from the homozygous state. 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. ... Lethal white syndrome (LWS)

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Overo lethal white syndrome (OLWS)
First posted: May 15, 2015
Last update: May 15, 2015