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American Paint Horse
Overo Lethal White Foal Syndrome
Related terms: Ileocolonic aganglionosis; aganglionic megacolon
Related conditions: Hirschsprung disease (humans)
Outline: American Paint horses are known for their bold and colourful markings; the overo pattern describes irregular white colouration on the abdomen of the horse. There is a genetic mutation within this line of horses which means that some may inherit a disease called overo lethal white foal syndrome, which causes a lack of pigment in the hair and skin of affected animals, and severe intestinal tract abnormalities.
Affected foals may appear normal at birth but have an underdeveloped and contracted intestinal tract, and are not able to move ingested material through the intestinal tract or defecate. Clinical signs of pain and colic can start to be shown within 12 hours of birth The condition can be extremely painful and distressing and all affected foals die within a few days of birth due to rupture of the bowel or bacterial infection. There is no treatment for the condition and foals suspected of having lethal white syndrome are usually humanely euthanized by a veterinarian.
Summary of Information
(for more information click on the links below)
1. Brief description
American Paint horses are known for their bold and colourful markings; the overo pattern describes irregular white colouration on the abdomen of the horse.
Overo lethal white foal syndrome, is an inherited condition in Paint horses in which affected animals have severe intestinal tract abnormalities which cause a non-functioning colon. Affected horses also have a characteristic appearance caused by an absence of melanocytes, pigment producing cells in the hair and skin, and this results in an all-white, or nearly all-white, coat colour with pink skin and blue eyes. Some foals may also be deaf.
Affected foals may appear normal at birth and are able to stand and will suckle. The abnormal, lack of nerve supply to the intestinal tract, however means that the normal peristaltic waves that move food through the gut is impaired and affected foals are not able to move ingested material through the intestinal tract and foals are not able to defecate. Signs of extreme abdominal pain (colic) begin to appear within twelve hours of birth, and foals show other signs of distress including sweating, rapid breathing, violent thrashing and body rolling. In affected animals, the intestinal tract is underdeveloped and contracted and portions of the small intestine may be distended with patchy or inflamed mucosal surfaces. All affected foals die within the first few days due to rupture of the bowel and resultant bacterial infection.
The characteristic appearance of affected foals caused by absence of melanocytes in the skin results from a genetic defect affecting neural crest cells, which are also responsible for the growth of nerve cells in the intestines. In the developing embryo, the neural crest is a part of a structure called the folding neural tube that goes on to form cell bodies for all neurons and supporting cells outside the central nervous system. As the embryo develops, neural crest cells migrate away from the neural tube and differentiate into various cell types, including both melanocyte and enteric (gut) neuron cells. A mutation in one of the genes that controls migration of these cells disrupts their development and leads to an absence of melanocytes (pigment) in the skin and hair, and the absence of neural cells in the gastrointestinal tract.
2. Intensity of welfare impact
The intestinal tract abnormalities associated with this disease cause intestinal blockage and severe abdominal cramping and pain (colic) in affected animals. The condition is extremely painful and distressing and all affected foals die within a few days of birth. There is no treatment for the condition and foals suspected of having lethal white syndrome are usually humanely euthanized by a veterinarian.
3. Duration of welfare impact
Affected foals appear normal at birth, but the clinical signs of the condition occur within 12 hours. The condition is rapidly progressive, and ultimately fatal within a few days of birth.
4. Number of animals affected
The frequency of heterozygote carriers of the mutation responsible for overo lethal white foal syndrome (these animals are unaffected but have the potential to produce affected offspring) was 10.7% in 180 American Paint horses overall (Tryon et al 2009), but in certain overo coat colours, there was a very high incidence (>95%) of heterozygote carriers (frame overo, highly white calico overo and frame blend overo coat patterns). Matings between two carrier horses will have a 1 in 4 chance of producing an affected offspring.
5. Diagnosis
The inability to defecate is noticeable within 12 hours after birth, and this coupled with the characteristic white coat colour with pink skin will suggest the foal has overo lethal white foal syndrome. Since the progression of the condition is usually rapid, diagnosis is often made post-mortem, with abnormalities found in the gastrointestinal tract.
The condition can also be definitively diagnosed using a genetic test that can identify the genetic mutation in homozygous affected horses and heterozygous unaffected carriers.
6. Genetic
A genetic mutation found on the endothelin-B receptor gene (EDNRB) is responsible for overo lethal white foal syndrome. The mutation causes ineffective migration of neural crest cells in the developing embryo, which leads to a lack of melanocytes (pigment cells) and enteric nerve cells.
Overo lethal white foal syndrome is inherited as an autosomal recessive trait in American Paint horses. Horses that have two copies of the gene mutation, one from each parent, will be homozygous affected and have this lethal condition. Horses which have one copy of the gene mutation, one from one of the parents, are heterozygous carriers do not have the lethal white syndrome, but do have the overo coat colour pattern and are likely to be deaf. The mating of two overo horses results in a 25% chance of the offspring being homozygous affected with lethal white syndrome, whilst 50% will be heterozygous carriers for the condition and a further 25% will be clear of the genetic mutation (normal).
7. How do you know if an animal is a carrier or likely to become affected?
Horses that are homozygous for the condition die shortly after birth and so they will never reach sexual maturity and be mated.
A genetic test can identify the genetic mutation responsible for overall lethal white foal syndrome and provides the most accurate way to determine whether white-patterned horses can produce affected foals. It can detect homozygous (two copies of the mutation) affected horses and heterozygous carriers (unaffected; one copy of the mutation), as well as non-affected (no gene mutation) horses.
Overo white patterning, especially frame overo, is strongly associated with the genetic mutation associated with overo lethal white foal syndrome. However, in heterozygous (unaffected) carriers, the white coat phenotype may be suppressed by other colour genes or because of fusion with additional white pattern genes and so the characteristic coat and skin colour is not a definite predictor of the condition. Horses with overo Paint bloodlines should be DNA tested for the gene mutation responsible for the condition.
8. Methods and prospects for elimination of the problem
Horses which are homozygous affected by this condition will not be bred from, since they die before reaching sexual maturity. To reduce the prevalence of this recessive inherited disorder, genetic screening for carriers is recommended for all American Paint horses that may be bred from, especially those with overo colouring or if there is a history of this condition in siblings, siblings of parents or other relatives. The mating of two carriers together should be avoided, since a quarter of the horses they produce will suffer from the condition and half will be carriers. Only horses without the mutated gene should be used for breeding. If carriers are bred, they should only be mated with other animals that are known not to be carriers, and breeders should note that this practice will result in the gene being maintained within the population.
For further details about this condition, please click on the following:
(these link to items down this page)
- Clinical and pathological effects
- Intensity of welfare impact
- Duration of welfare impact
- Number of animals affected
- Diagnosis
- Genetics
- How do you know if an animal is a carrier or likely to become affected?
- Methods and prospects for elimination of the problem
- Acknowledgements
- References
1. Clinical and pathological effects
American Paint horses are known for their bold and colourful markings. The coat colour patterns of Paint horses may be a combination of white and any other colour (eg black, bay, brown, roan), and the markings vary in size and shape over the horse’s body. Overo describes irregular white colouration on the abdomen of the horse (Figure 1). There are three sub-types of overo pattern, namely frame overo, sabino and splashed white, and each has distinct white coat patterns.
Figure 1. A frame overo horse with irregular white patches. Image is reproduced with permissions under the Creative Commons Attribution 2.5 Generic license, with thanks to www.horsevet.co.uk https://commons.wikimedia.org/wiki/File:Overo2.jpg)
There is a genetic mutation within this line of horses that means that some may inherit a disease, called overo lethal white foal syndrome, which causes severe intestinal tract abnormalities and results in the early death of affected animals.
Affected horses also have a characteristic appearance caused by an absence of melanocytes, pigment producing cells in the hair and skin, and this results in an all-white or nearly all-white coat colour with pink skin and blue eyes. Some foals may also be deaf.
Animals with overo lethal white foal syndrome may appear normal at birth and are able to stand and will suckle as normal. (Vonderfecht et al 1983, McCabe et al 1990). Soon after birth, healthy foals produce the first stool – meconium – that is composed of materials ingested during time spent in the uterus. In foals affected with overo lethal white syndrome, intestinal tract abnormalities cause a non-functioning colon and foals are not able to defecate (Hultgren 1982). The meconium becomes impacted high in the intestine and is unable to be expelled (McCabe et al 1990). Signs of extreme abdominal pain (colic) begin to appear within the first day, and foals may show sweating, rapid breathing, violent thrashing and body rolling. All affected foals die within the first few days of birth due to rupture of the bowl, or poisoning/toxaemia of the blood supply through build-up of toxic waste material or absorption of contaminated material in the gut and intestines (Hultgren 1982).
The signs of overo lethal white foal syndrome are confined to the gastrointestinal tract. The enteric nervous system (digestive nervous system) drives normal digestive function automatically, producing peristaltic waves that moves ingested food through the gut, and also communicates with the central nervous system. There are two major nerve supplies to the muscular layer of the gut. The myenteric plexus controls digestive tract motility, and the submucous plexus, buried within the submucosa, help to regulate gastrointestinal blood flow, and control epithelial cell functions of secretion of digestive enzymes and absorption of materials from the gut. In foals affected by lethal white syndrome, there is an absence of mysenteric and submucosal ganglia – clusters of nerve cells – in the large intestine and various parts of the small intestine, with the ileum most severely affected of the small intestines (Hultgren 1982, Vonderfecht et al 1983). The intestinal tract is underdeveloped and contracted, and foals are unable to move ingested material along their intestinal tract. As a result, they develop paralytic ileus, intestinal blockage in the absence of actual physical obstruction. Intestinal rupture and inflammation of the peritoneum (lining of the abdominal cavity) caused by bacterial infection (peritonitis) can occur. Clinical findings on surgical exploration of the abdomen or on post-mortem include a distended jejunum and ileum with green mucinous material and patchy or inflamed mucosal surfaces. The colon and rectum are reduced in size and may be pale in colour (Vonderfecht et al 1983).
The pathogenesis of overo lethal white foal syndrome is a result of a genetic defect that affects neural crest cells in the developing embryo. The neural crest is a part of the folding neural tube that subsequently forms cell bodies for all neurons and supporting cells outside the central nervous system. In a process called neurulation, a structure called the neural plate folds in upon itself to form a neural tube, and this later differentiates into the spinal cord and the brain. During development neural crest cells are separated from the neural tube and migrate away from the dorsal midline. When these cells reach their target destination, they differentiate into various cell types (Parry 2005). Both melanocytes (pigment-producing cells found in hair follicles and skin) and myenteric ganglia cells, nerve cells associated with the intestinal tract, originate from the neural crest. The migration of cells that descend from the neural tube is carefully controlled by regulatory genes, including endothelian receptor type B (EDNRB). A mutation in the middle of the EDNRB gene (IIe118Lys) disrupts the function of the protein, limiting the migration of both melanocyte and enteric (gut) neuron precursors (Santschi et al 1998, Metallinos et al 1998). This leads to the absence of melanocytes (pigment) in the skin and eyes, and the absence of neural cells in the gastrointestinal tract – the absence of which causes the abnormality in normal intestinal tract function.
2. Intensity of welfare impact
The intestinal tract abnormalities associated with this condition cause severe intestinal blockage and abdominal cramping and pain (colic) in affected animals. The inability to defecate also causes severe abdominal pain and discomfort, and horses may be restless, and show excessive sweating and breathing difficulties. They may also violently paw and roll on the ground in pain. The condition is extremely painful and distressing and all affected foals die within a few days of birth. There is no treatment for the condition and foals suspected of having lethal white syndrome are usually humanely euthanized by a veterinarian.
3. Duration of welfare impact
Affected foals appear normal at birth, but the clinical signs of the condition occur within 12 hours (Vonderfecht et al 1983). The condition is rapidly progressive, and ultimately fatal within a few days of birth.
4. Number of animals affected
The frequency of heterozygote carriers of the mutation for overo lethal white foal syndrome (that are unaffected but have the potential to produce affected offspring) was found to be 10.7% in 180 American Paint horses overall (Tryon et al 2009). The mutation was not detected in 55 solid coloured horses from breeds without white patterning (Santschi et al 2001). However, a very high incidence (>95%) of heterozygote carriers, which if mated with another carrier would have a 1 in 4 chance of producing an affected offspring, was found in specific overo coat patterns, namely frame overo, highly white calico overo and frame blend overo coat patterns (Santschi et al 2001). Horses with other overo white-coated patterns have a low incidence of heterozygotes (<21%), these include tobiano, sabino, minimally blend overo and breeding stock solid Santschi et al 2001).
5. Diagnosis
Signs suggestive of a horse having inherited overo lethal white foal syndrome are a white coat colour with pink skin as well as problems defecating, which is noticeable within 12 hours after birth. Since the progression of the condition is usually rapid, diagnosis is often made post-mortem, with abnormalities found in the gastrointestinal tract. Histologically, there is a lack of ganglion cells in the large and small intestines (Vonderfecht et al 1983).
The condition can also be definitively diagnosed using a genetic test which can identify the genetic mutation in homozygous affected horses and heterozygous unaffected carriers (Metallinos et al 1998).
Although white coat colour and blue eyes are characteristic of this condition, a diagnosis cannot be made on coat colour alone. Healthy horses can be produced with white coats, pink skin and blue eyes eg Sabino-white horses, or double-cream dilutes. Black tails and muzzle markings have been recorded in affected foals (Vonderfecht et al 1983), and horses with non-overo coat patterns may be unaffected carriers (heterozygous) for the condition.
6. Genetics
Genetic conditions which affect more than one physical trait are termed pleiotropic – in the case of overo lethal white foal syndrome, both pigment cells and enteric nerve cells are disrupted. A genetic mutation found on the endothelin-B receptor gene (EDNRB) is responsible for overo lethal white foal syndrome (Metallinos et al 1998, Yang 1998). The mutation causes ineffective migration of neural crest cells in the developing embryo which leads to a lack of melanocytes (pigment cells) and enteric nerve cells, leading to the condition whereby horses have all- or near- white coat colour and a gastrointestinal tract abnormalities.
Overo lethal white foal syndrome is inherited as an autosomal recessive trait in American Paint horses (McCabe et al 1990). Horses, which have two copies of the gene mutation, one from each parent, will be homozygous affected and have this lethal syndrome. Since these horses die shortly after birth, they will never reach sexual maturity and produce offspring. Horses, which have one copy of the gene mutation, one from one of the parents, are heterozygous carriers. They will not have the lethal white syndrome, but will have the overo coat colour pattern. The mating of two overo horses will result in a 25% chance of the offspring being homozygous affected with lethal white syndrome, whilst 50% will be heterozygous carriers for the condition and a further 25% will be clear of the genetic mutation (normal).
7. How do you know if an animal is a carrier or likely to become affected?
Overo white patterning, especially frame overo, is strongly associated with the genetic mutation that causes overo lethal white foal syndrome (Metallinos et al 1998, Santschi et al 2001). However, heterozygous carriers (which show no signs of the disease but carry one copy of the mutated gene and can pass it on) have been reported in horses with no recognised overo coat. In carriers, the white coat phenotype may be suppressed by other colour genes or because of fusion with additional white pattern genes so the characteristic coat and skin colour is not a definite predictor of the condition. Horses with overo Paint bloodlines should be DNA tested for the gene mutation responsible for the condition.
Even for horses with the clinical phenotype (all or near-all white coats, blue eyes and pink skin), it is advisable to wait for clinical signs of the condition to develop (no defecation, colic) before making a decision about euthanizing the animal, since these phenotypic traits can be produced by other genes involved in coat colour and pattern which are not related to the lethal white syndrome.
A genetic test can identify the genetic mutation responsible for overall lethal white foal syndrome and provides the most accurate way to determine whether white-patterned horses can produce affected foals. It can detect homozygous (two copies of the mutation) affected horses and heterozygous carriers (unaffected; one copy of the mutation), as well as non-affected (no gene mutation) horses.
8. Methods and prospects for elimination of the problem
Horses which are homozygous and affected by this condition will not be bred from, since they die before reaching sexual maturity. To reduce the prevalence of this recessive inherited disorder, genetic screening for carriers is recommended for all American Paint horses that may be bred from, especially those with overo colouring or if there is a history of this condition in siblings, siblings of parents or other relatives. The mating of two carriers together should be avoided, since a quarter of the horses they produce will suffer from the condition and half will be carriers. Only horses without the mutated gene should be used for breeding, or at least carriers should not be mated with other carriers and breeders should note that this practice will result in the gene being maintained within the population.
9. Acknowledgements
UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.
10. References
Hultgren BD (1982) Ileocolonic aganglionosis in white progeny of overo spotted horses. Journal of the American Veterinary Medical Association 180: 289–92
McCabe L, Griffin LD, Kinzer A, Chandler M, Beckwith JB and McCabe ER (1990) Overo lethal white foal syndrome: equine model of aganglionic megacolon (Hirschsprung disease). American Journal of Medical Genetics 36: 336–40
Metallinos AT, Bowling DL and Rine J (1998) A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung Disease. Mammalian Genome 9: 426–431
Parry NMA (2005) Overo Lethal White Foal Syndrome. Compendium on Continuing Education for the Practicing Veterinarian - North American Edition 27: 945–950
Santschi EM, Purdy AK, Valberg SJ, Vrotsos PD, Kaese H and Mickelson JR (1998) Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses. Mammalian Genome 9: 306–309
Santschi EM, Vrotsos PD, Purdy AK and Mickelson JR (2001) Incidence of the endothelin receptor B mutation that causes lethal white foal syndrome in white-patterned horses. American Journal of Veterinary Research 62: 97–103
Tryon RC, Penedo MCT, McCue ME, Valberg SJ, Mickelson JR, Famula TR, Wagner ML, Jackson M, Hamilton MJ, Nooteboom S and Bannasch DL (2009) Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter Horses. Journal of the American Veterinary Medical Association 234: 120–5
Vonderfecht SL, Bowling AT and Cohen M (1983) Congenital Intestinal Aganglionosis in White Foals. Veterinary Pathology Online 20: 65–70
Yang G (1998) A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease. Human Molecular Genetics 7: 1047–1052
© UFAW 2016
Credit for main photo above:
http://depositphotos.com/46267487/stock-photo-gorgeous-brown-and-white-stallion.html.
