Lethal white syndrome
Template:Short description Template:Infobox medical condition (new) 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; affected foals die within a few days. Because the death is often painful, such foals are often humanely euthanized once identified. The disease is particularly devastating because foals are born seemingly healthy after being carried to full term.<ref name=apha>Template:Cite journal </ref>
The disease has a similar cause 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, which 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 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. Also, different genetic mechanisms produce healthy white foals and have no connection to LWS, another reason for genetic testing of potential breeding stock. Some confusion also occurs because the term overo is used to describe a number of other non tobiano spotting patterns besides the frame pattern. Though no treatment or cure for LWS foals is known, a white foal without LWS that appears ill may have a treatable condition.
Signs
Unlike the premature births and stillborn or weak foals of some coat color dilution lethals, foals born with lethal white syndrome appear to be fully formed and normal.<ref name=1a>Template:Cite journal</ref><ref name=3a>Template:Cite journal</ref> The coat is entirely or almost entirely white with underlying unpigmented pink skin.<ref name=1a/><ref name="3a" /><ref name=2a>Template:Cite journal</ref> If pigmented regions are present, they may be any color, and are most common around the muzzle, underside of the barrel, and the hindquarters or tail.<ref name=1a/> The eyes are blue. A few lethal white foals have been shown to be deaf.<ref name=3a/><ref name=4a>Template:Cite journal</ref>
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.<ref name=3a/> Signs of colic begin to appear within the first day,<ref name=1a/> and all foals with LWS die within the first few days of life.<ref name=2a/> The painful and inevitable death that follows usually prompts veterinarians and owners to euthanize foals suspected of having lethal white syndrome.<ref name=6a>Template:Cite web</ref><ref name=13a>Template:Cite web</ref>
Death is caused by an underdeveloped part of the digestive system. The large intestine of the horse comprises the cecum, the colon, and the rectum.<ref name="Digestive system">Template:Cite web</ref> Necropsies on LWS foals reveal a pale, underdeveloped colon<ref name=1a/> and intestinal obstruction (impaction).<ref name=2a/> 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.<ref name="1a" /><ref name="3a" /><ref name="2a" />
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.<ref name=3a/> All LWS foals test homozygous for a genetic abnormality.<ref name=5a>Template:Cite journal</ref>
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.<ref name=2a/> 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.<ref name=thiruvenkadan2008>Template:Cite journal</ref>
Such regulatory genes include endothelin receptor type B (EDNRB). A mutation in the middle of the EDNRB gene, Ile118Lys, causes lethal white syndrome.<ref name=4a/><ref name=19a>Template:Cite journal</ref> In this mutation, a "typo" in the DNA mistakes isoleucine for lysine.<ref name=19a/> 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.<ref name=HTHZ>Metallinos DL, Bowling AT, Rine J (1998). "In three unrelated lethal white foals, the EDNRB gene contained a 2-bp nucleotide change leading to a missense mutation (I118K) in the first transmembrane domain of the receptor, a highly conserved region of this protein among different species. Seven additional unrelated lethal white foal samples were found to be homozygous for this mutation. No other homozygotes were identified in 138 samples analyzed, suggesting that homozygosity was restricted to lethal white foals. All (40/40) horses with the frame overo pattern (a distinct coat color pattern that is a subset of overo horses) that were tested were heterozygous for this allele, defining a heterozygous coat color phenotype for this mutation."</ref>
To produce a foal with LWS, both parents must be heterozygotes or carriers of the mutated gene.<ref name="13a" /><ref name=9a>Template:Cite web</ref><ref name=12a>Template:Cite news</ref> Without genetic testing, some carriers are misidentified as having white markings due to another gene, while some are even classified as solids.<ref name=3a/>
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.<ref name=4a/><ref name=6a/><ref name=13a/>
Heterozygotes
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Horses heterozygous for the Ile118Lys mutation on the equine EDNRB gene—carriers of lethal white syndrome—usually exhibit a white-spotting pattern called "frame", or "frame overo".<ref name=4a/><ref name=13a/><ref name=5a/><ref name=9a/> Frame is characterized by jagged, sharply defined, horizontally oriented white patches that run along the horse's neck, shoulder, flank, and hindquarters. The frame pattern by itself does not produce white markings that cross the back, or affect the legs or tail. It does, however, often produce bald faces and blue eyes.<ref name=4a/><ref name=13a/><ref name=5a/> The term "frame" describes the effect of viewing a frame-patterned horse from the side: the white markings appear to be "framed" by a dark-colored border.<ref name=13a/> To date, animals which are heterozygous carriers do not exhibit health concerns associated with carrier-only status.<ref>Template:Cite web</ref>
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.<ref name=5a/> 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.<ref name=5a/> However, over one-quarter of Paints registered in the "overo" category were not frames, and conversely, 10% of horses registered as tobiano also carried frame genetics.<ref name=5a/> The difficulty in accurately identifying frames has contributed to the accidental breeding of LWS 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.<ref name=remarquez>Template:Cite web</ref> A Quarter Horse mare tested positive for the gene after she and a frame Paint stallion produced a LWS foal; the mare's markings were a thin blaze with a disconnected white spot in the right nostril, with no other white markings.<ref name=3a/> One major study identified two miniature horses that were completely unmarked, but were positive for the Ile118Lys gene.<ref name=5a/>
Multiple theories are given 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.<ref name="Metallinos">Template:Cite journal</ref><ref>Template:Cite journal</ref> Several research groups have suggested that other, "suppressor" genes may limit the expression of frame-pattern white spotting.<ref name=9a/><ref name=15a>Template:Cite journal</ref>
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.<ref name="Metallinos"/> Other white-spotting genes include splashed white or "splash", sabino, and "calico".<ref name=5a/> 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.<ref name=BSwhite>Santschi EM, Mickelson JR (2001). 80% of breeding stock white (all-white horses of Paint pedigree) were genotyped N/L for Endothelin Receptor B.</ref>
Ambiguous terminology has also contributed to the confusion surrounding this disease. Currently, the American Paint Horse Association categorizes horses as tobiano, solid, "overo", and tovero.<ref name="Guidebook">Template:Cite web</ref> The association breaks down "overo" into three categories: Frame, Splash and Sabino.<ref name="Guidebook"/> In the past, "overo" was used even more loosely, to refer to spotted animals that were "Paint, but not tobiano".<ref name="Guidebook"/> However, no fewer than four—and likely many more—genetically distinct patterns are included under the term "overo".<ref name=5a/><ref name=15a/><ref name=7a>Template:Cite news</ref> 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.<ref name=10a>Template:Cite web</ref> 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.<ref name="UCDVGL">Template:Cite web</ref>
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.<ref name=11a>Template:Cite web</ref> This helps to account for allegedly solid horses producing spotted offspring, called cropouts.<ref name=13a/>
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.<ref name=2a/> However, "overo" refers to several genetically unrelated white-spotting patterns, and only the frame pattern is indicative of the syndrome.<ref name=13a/><ref name=5a/><ref name=9a/> 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",<ref name="Guidebook"/> which is technically correct, but only because the term "overo" also encompasses splash and sabino patterns, as well as frame.<ref name="Guidebook"/>
Homozygotes
Homozygotes for the Ile118Lys mutation on the equine endothelin receptor type B gene have lethal white syndrome.<ref name=4a/><ref name=5a/> In any crossing of two carrier parents, the statistical probability of producing a solid-colored, living foal is 25%; a 50% chance exists for a frame-patterned, living foal; and a 25% chance exists of a LWS foal.<ref name=12a/>
Producing frame color patterns without producing lethal white
Spotted coat colors, including frame, are popular and sought after by breeders.<ref name=brooksdissert>Template:Cite thesis</ref> While many lethal white syndrome foals are accidentally produced when breeders cross two untested cryptic frames, or a known frame and a cryptic frame, some are produced by the intentional breeding of two known frames, whether out of ignorance or indifference. Producing a foal with LWS is now completely avoidable, because most major animal genetics labs now offer the DNA test for it. Whether a horse visually appears to have the frame pattern or not, testing horses of frame or "overo" lineage is highly recommended. The statistical likelihood of producing a living, frame-patterned foal by crossing two frames is 50%, the same odds of producing a living, frame-patterned foal from a frame-to-nonframe breeding which carries no risk of producing a lethal white syndrome foal.<ref name=12a/> Therefore, breeding two frame overos conveys no benefit to breeders hoping to produce another frame overo.
Dominant or recessive?
Lethal white syndrome has been described by researchers as both dominantly and recessively inherited.<ref name=finno2008>Template:Cite journal</ref><ref name=missense2>Metallinos et al 1998. "Based on the strength of this association and its complete compatibility with simple mendelian recessive inheritance, we inferred that Lethal White Foal Syndrome was tightly linked to the mutation."</ref><ref name=thiruvenkadan2>Thiruvenkadan et al 2008. "The overo lethal syndrome due to dominant homozygotes (OO) at the overo locus results in death of the foals a few days after birth."</ref> Lethal white syndrome is described as recessive because heterozygotes (written Oo or N/O) are not affected by intestinal agangliosis. However, if the frame pattern trait is included, inheritance of the trait follows an incomplete dominant pattern. The concept of "recessive" and "dominant" antedate molecular biology and technically apply only to traits, not to genes themselves. In pleiotropic conditions, such as LWS, the application of "recessive" or "dominant" can be ambiguous.<ref name=nomenclature2000>Template:Cite journal</ref>
A separate issue is the nomenclature applied to the frame pattern itself. While it follows a dominant pattern of inheritance, deviations occur.<ref name=14a>Template:Cite journal</ref> The majority of horses with the Ile118Lys mutation do exhibit the recognizable frame pattern, but a small percentage are too modestly marked to be classified as "spotted" by breed registries. Such "solid" horses, bred to a solid partner, can produce classically marked frames.<ref name=APHAGE3-2>Template:Cite web</ref> The "crop-out" phenomenon can make frame appear to follow a recessive mode of inheritance.
Prevalence
The gene for LWS is most common in the American Paint Horse, but occurs in any breed that may carry frame genetics, including American Quarter Horses, Appaloosas, Thoroughbreds, Morgan horses, miniature horses, Tennessee Walking Horses, and mustangs, as well as horses that are descended from these breeds.Template:Citation needed Only two Morgan horses have been identified as frame overos.<ref>Laura Behning. "Other Colors". Morgan Colors. Retrieved 2009-05-03.</ref> Breeds that do not carry genes for the frame pattern also do not carry LWS.<ref>Template:Cite web |title=Other Colors |work=Morgan Colors |author=Laura Behning |accessdate=2009-05-03</ref>
Lethal white mimics
Not all white, blue-eyed foals are affected with LWS. Other genes can produce healthy pink-skinned, blue-eyed horses with a white or very light cream-colored coat.<ref name=12a/> For a time, some of these completely white horses were called "living lethals", but this is a misnomer. Before reliable information and the DNA test were available to breeders, perfectly healthy, white-coated, blue-eyed foals were sometimes euthanized for fear they were lethal whites,<ref name=12a/> an outcome which can be avoided today with testing and a better understanding of coat color genetics or even waiting 12 hours or so for the foal to develop clinical signs. The availability of testing also allows a breeder to determine if a white-coated, blue-eyed foal that becomes ill is an LWS foal that requires euthanasia or a non-LWS foal with a simple illness that may be successfully treated.
- Double-cream dilutes such as cremello, perlinos, and smoky creams, have cream-colored coats, blue eyes, and pink skin. The faint cream pigmentation of their coats can be distinguished from the unpigmented white markings and underlying unpigmented pink skin. A similar-looking "pseudo double dilute" can be produced with help from the pearl gene or "barlink factor" or the champagne gene.Template:Citation needed
- The combination of tobiano with other white-spotting patterns can produce white or nearly white horses, which may have blue eyes.<ref name=phj>Template:Cite web
</ref>
- Sabino horses that are homozygous for the sabino-1 (Sb-1) gene are often called "sabino-white", and are all- or nearly all-white. Not all sabino horses carry Sb-1.<ref name="UCDVGL"/>
- Dominant white genetics are not thoroughly understood, but are characterized by all- or nearly all-white coats.
Analogous conditions
From very early in research into its genetics,<ref name=2a/> LWS has been compared to Hirschsprung's disease in humans, which is also caused by mutations on the EDNRB gene. Various polymorphisms on this gene result in intestinal agangliosis, in some cases attended by unusual pigmentation of the skin and eyes, and deafness. The occasionally attendant pigmentation condition in humans is called Waardenburg-Shah syndrome.<ref name=4a/>
The terms "piebald-lethal" and "spotting lethal" apply to similar conditions in mice and rats, respectively, both caused by mutations on the EDNRB gene.<ref name=17a>Template:Cite journal</ref><ref name=18a>Template:Cite journal</ref> Only lethal in the homozygous state, the mutations are associated with white-spotted coats, deafness, and megacolon caused by intestinal agangliosis.<ref name=4a/>
See also
External links
- Canadian Veterinary Journal paper which includes a picture of a foal with OLWS