This disease has been observed in Holstein and Guernsey cattle and usually does not appear until the animals are adults. A recent report described it in a Canadian Hereford bull with an early onset between 1 and 2 years of age.1 It is a particular problem in mature bulls maintained in artificial insemination centers. In the early stages the signs are apparent only on rising, the hindlimbs being stretched out behind and the back depressed. Marked tremor of the hindquarters may be noted. Initially the attacks persist only for a few seconds but are of longer duration as the disease progresses and may eventually last for up to 30 minutes. Movement is usually impossible during the attacks. The tetanic episodes fluctuate in their severity from time to time but there is never any abnormality of consciousness. Lesions of the vertebrae have been recorded but no lesions have been found in the nervous system. Idiopathic muscle cramps have been suggested as a cause. The disease is familial and the mode of inheritance appears to be by inheritance of a single recessive factor with incomplete penetrance.
Administration of the spinal cord depressant, mephenesin (3–4 g/100 kg body weight given orally in 3 divided doses and repeated for 2–3 days) controls the more severe signs. A single course of treatment may be effective for some weeks.
The defect is recorded in Jersey and Hereford cattle. Affected calves are normal at birth but develop signs 2–5 days later. The signs commence with incoordination and bulging of the eyes and a tendency to deviation of the neck causing the head to be held on one side. Subsequently, the calves are unable to stand and on stimulation develop a tetanic convulsion in which the neck, trunk, and limbs are rigidly extended and show marked tremor. Each convulsion is of several minutes’ duration. Affected calves may survive for as long as a month if nursed carefully. There are no gross or histological lesions at necropsy. Inheritance of the defect is conditioned by a single, recessive character.
This congenital defect of the nervous system has been reported only in Poll Hereford cattle or their crossbreds and appears to be transmitted by inheritance in an autosomal recessive pattern. A similar disease has been tentatively recorded in Peruvian Pasos horses.2 At birth affected calves are unable to sit up or rise and are very sensitive to external stimuli, manifested by extreme extensor spasm, including fixation of thoracic muscles and apnea, especially if lifted and held upright. The response is one of hyperesthesia with myoclonic jerks of skeletal muscles in response to external stimuli or spontaneously.3 The intellect of the calves seems unaffected, vision is normal, they drink well, and can be reared but at a great cost in time. Intercurrent disease is common and calves usually die of pneumonia or enteritis before they are 1 month old.
All affected calves have subluxations of the hip joints or epiphyseal fractures of the femoral head caused by muscle spasms in the fetus. Their gestation length is shorter than that of normal calves by 9 days.
There are no microscopic lesions in the central nervous system, but there is a biochemical defect, severe alterations in spinal cord glycine-mediated neurotransmission.4 The specific and marked defect in glycine receptors and the increase in neuronal uptake of glycine are accompanied by a change in the major inhibitory system in the cerebral cortex. It has also been shown that there is a specific and marked deficit of [3H] strychnine-binding sites in the spinal cord. The disease needs to be differentiated from two other congenital, presumed hereditary, diseases of newborn Herefords – maple syrup urine disease and ‘congenital brain edema’ – in which spongy degeneration of the CNS is accompanied by severe edema of the gray and white matter. These two diseases are assumed to represent those cases of congenital disease, originally bracketed with inherited congenital myoclonus, in which there was vacuolation of nervous tissue in the central nervous system.
Two inherited forms of congenital posterior paralysis are recorded in cattle. In Norwegian Red Poll cattle posterior paralysis is apparent in affected calves at birth. Opisthotonos and muscle tremor are also present. No histological lesions have been found. The disease is conditioned by an inherited recessive factor. In Red Danish and Bulgarian Red cattle a similar condition occurs but there is spastic extension of the limbs, particularly the hindlimbs, and tendon reflexes are exaggerated. Histological examination has revealed degenerative changes in midbrain motor nuclei. Both defects are lethal because of prolonged recumbency.
An inherited posterior paralysis has been recorded in several breeds of swine in Europe. Affected pigs are able to move their hindlimbs but are unable to stand on them. They are normal in other respects. Degeneration of neurons is evident in cerebral cortex, midbrain, cerebellum, medulla, and spinal cord. The disease is conditioned by the inheritance of a recessive character. An inherited progressive ataxia is also recorded in Yorkshire pigs.
This disease has been observed in goats and possibly in a horse. Because of its great similarity to Thomsen’s disease (myotonia congenita) of humans, affected goats have been used in experimental studies to determine the nature of the disease. There is no apparent defect of the nervous system and the condition is thought to be due to abnormality of the muscle fibers. The specific defect is thought to be one of generalized cell membrane abnormality including muscle fibers. Affected animals run when startled but quickly develop extreme rigidity of all four limbs and are unable to move. Relaxation occurs in a few seconds and the animal can then move again. Signs are not usually present until some time after birth and may vary from day to day for no apparent reason. They tend to diminish immediately before and after parturition. Clinical signs disappear when water is withheld from affected goats for 2–3 days but reappear when drinking is permitted. The disease is inherited but the mode of inheritance is unknown.
Congenital tremor of pigs has a multiple etiology and some of the causes are not yet identified. For this reason the disease as a whole is dealt with in Chapter 36. The inherited diseases are noted here. There are two of them, congenital tremor type A-IV of British Saddleback pigs, and congenital tremor type A-III, a sex-linked inherited form of cerebrospinal hypomyelinogenesis of Landrace pigs. The A-IV disease is characterized by the presence of poorly myelinated axons in all parts of the central nervous system. The specific defect in A-IV is one of fatty acid metabolism. The structural abnormalities in the A-III disease have been identified; splayleg is a common accompaniment.
Both diseases are characterized by muscle tremor, incoordination, difficulty in standing, and some squealing. The A-III disease occurs only in males. Both are inherited as recessive characters.
This disease has been recorded in Shorthorn, in which it is not manifested until the first pregnancy or lactation, in Jerseys, in which it may appear at 6–12 months of age, and in German Brown Swiss.1 Defective vision is the first sign and is followed by severe protrusion and anteromedial deviation of both eyeballs. The defects may get worse over a long period and appear to be inherited in a recessive manner, with relative absence of neurons in the abducens nerve.
This is an inherited defect of Finnish Ayrshire cattle characterized by a tremor-like, synchronous movement of the eyeballs. The tremor has small amplitude (1–2 mm) and fast (200/min) rate and is usually vertical. It is present at all times, there is no sign of impaired vision, and the eye reflexes are normal. The condition is a blemish rather than a disease because there is no functional deficiency.
Idiopathic epilepsy has been reported as an inherited condition in Brown Swiss cattle and appears to be inherited as a dominant character. Typical epileptiform convulsions occur, especially when the animals become excited or are exercised. Attacks do not usually commence until the calves are several months old and disappear entirely between the ages of 1 and 2 years.
Affected horses, including Shetlands, Miniature Horses,1 and Suffolks, suffer recurrent episodes of several minutes duration during which they fall and lie motionless, without voluntary or involuntary movements except respiratory and eye movements. Between episodes there is no clinical abnormality. Handling or the excitement of feeding may precipitate an attack, and a sharp blow may terminate one.
There are strong indications from field evidence that both degenerative arthropathy, in which the hip joint is principally involved, and degenerative osteoarthritis, affecting particularly the stifle joint, are inherited in cattle. In both diseases other factors, particularly nutritional deficiency and the stress of lactation, exert an important influence on the appearance of the clinical disease, and in degenerative arthropathy, described in the chapter on nutritional deficiency diseases, there is no clear evidence that it is in fact inherited. On the other hand there is good evidence that osteoarthritis can be inherited, at least in Holstein-Friesian and in Jersey cattle.
In inherited degenerative osteoarthritis, in which the stifle joints are most severely affected, there is usually a gradual onset of lameness in both hindlimbs in aged animals of both sexes. Occasionally only one limb appears to be involved. Progression of the disease takes place over a period of 1–2 years and is evidenced by failure to flex the limb, resulting in the foot not being lifted high from the ground. Crepitation in the stifle joint can be heard and felt, the muscles of the limb atrophy, and the joints are enlarged. Movement is slow, the hindlimbs at rest are placed further forward than normal, the stifles are abducted and the feet held together. Joint fluid can be aspirated and is clear and straw-colored. Appetite and milk yield remain normal until the late stages, except in cattle running at pasture.
At necropsy there is severe osteoarthritis involving particularly the stifle, with extensive erosion of the articular cartilages, great increase in synovial fluid, and the development of many osteophytes around the edges of the articular surfaces. Less severe changes are evident in other joints. It is suggested that the disease is conditioned by the inheritance of a single autosomal recessive character.
The term osteogenesis imperfecta covers a heterogeneous group of connective tissue diseases caused by quantitative or qualitative defects in Type 1 collagen.2
The disease is recorded as being inherited in Holstein-Friesian cattle and New Zealand Romney sheep.1
It is transmitted as an autosomal dominant trait. Calves are clinically abnormal at birth with the main presenting signs being bright pink teeth and slackness of the flexor tendons on all four feet so that they are unable to stand. The calves become progressively worse to the point where they cannot walk. The full list of abnormalities in this syndrome includes smaller than normal body size at birth, a dome-shaped cranial vault, and fragility of bones, manifested by multiple fractures occurring during birth. The defect is one of connective tissue cells so that there is a faulty production of collagen and intercellular cement. Radiological examination demonstrates growth-arrest lines and multiple fractures in the long bones, and thin dentine and enamel layers on the teeth which are pink because of the exposed condition of the enlarged pulp. The excessive mobility of the joints results from the small bulk of the ligaments and tendons.
A syndrome of simple bone fragility occurs in Charolais cattle and is called osteogenesis imperfecta.
The disease in New Zealand Romney sheep2 is similar to that in Holstein-Friesian cattle with additional lesions of thickness of the diaphyses and reduction in size of the medullary cavity, moderate brachygnathia inferior, subcutaneous edema, skin fragility, and a dark blue color of the sclera. It is inherited as an autosomal dominant trait, and was thought to have developed as a new mutation in the testicular cell line of the parent ram.2
Most inherited food animal dwarfs are chondrodysplastic; they occur commonly only in cattle and are of two kinds, snorter dwarfs and Dexter bulldog calves.
Snorter dwarfs are no longer important because of successful efforts in eliminating carriers of the gene. These calves are short-legged with short, wide heads and protruding lower jaws. The mandibular teeth may protrude 2–4 cm beyond the dental pad, preventing effective grazing and necessitating hand-feeding if the animal is to survive. There is protrusion of the forehead and distortion of the maxillae, and obstruction of the respiratory passages results in stertorous respiration and dyspnea. The tip of the tongue usually protrudes from the mouth and the eyes bulge. There is some variation between affected animals in their appearance at birth. In most cases the defects are as described above but they become more exaggerated as the calf grows. In addition abdominal enlargement and persistent bloat develop. The head is disproportionately large. The calves fail to grow normally and are about half the weight of normal calves of the same age.
The predominant form of the condition appears to be inherited as a simple recessive character, although the relationship of the ‘comprest’ types to the total syndrome is more complex. Heterozygotes vary widely in conformation but some of them show minor defects which may be attractive to cattle breeders who were seeking a chunkier, short-legged type of animal. For this reason, indiscriminate selection towards the heterozygote undoubtedly occurred, resulting in widespread dissemination of the character. Herefords and Aberdeen Angus are the breeds most commonly affected but similar dwarfs occur also in Holstein and Shorthorn cattle, and typical dwarf animals have been produced by mating heterozygous Aberdeen Angus and Herefords. Besides the shortness of limbs there is also a looseness of attachment of limbs and abnormal mobility of joints.
Bovine chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive defect with the phenotype of short limbs, joint abnormality, and ateliosis.1 Long bones of affected animals have insufficient endochondrial ossification with irregularly arranged chondrocyte, abnormal formation of cartilaginous matrix, and partial disappearance of the epiphyseal growth plates. The gene LBN is the causative gene for bovine chondrodysplastic dwarfism.1 The bovine fibroblast growth factor receptor 3 (FGFR3) gene is not the locus responsible for the defect.2
First recorded as bulldog calves in Dexter cattle, this inherited defect has since been observed in a variety of forms in other breeds, including Jerseys, Guernseys, Holsteins, and Japanese Brown cattle.3 Chondrodysplasia in the Holstein-Friesian breed sharing morphological features with the Dexter bulldog calves have been reported from the United States, the Netherlands, Great Britain, and recently in Denmark.4 Dexter bulldog type calves have occurred in French and Danish Holstein calves in a familial pattern related to the sire Igale Masc, and it is likely that the genetic disorder is present in the Holstein breed worldwide.4
Characteristic features of lethal chondrodysplasia (Dexter bulldog) calves in Australian Dexter cattle include abortion, disproportionate dwarfism, a short vertebral column, marked micromelia, a relatively large head with retruded muzzle, cleft palate and protruding tongue and a large abdominal hernia.5 Histological changes in limb bones are consistent with failure of endochondral ossification. Dexter chondrodysplasia is considered to be inherited in an incompletely dominant manner with the homozygous form producing the congenital lethal condition. Based on analysis of the contribution of three obligate heterozygotes whose semen has been widely used in artificial insemination in Australia, it is estimated that the heterozygote frequency is 19% within the registered Australian Dexter herd.5
Affected calves are often aborted but some reach full term and cause fetal dystocia because of the extreme hydrocephalus. The forehead bulges over a foreshortened face with a depressed, short nose. The tongue protrudes, the palate is cleft or absent, the neck is short and thick, and the limbs are shortened. Accompanying defects are fetal anasarca and hydrops amnii in the dam.
The defect is primarily chondrodystrophy rather than achondroplasia; the nasal bones and maxillae do not grow. Hydrocephalus develops because of the deformed cranium. In most breeds the condition is inherited as a simple recessive character but a dominant form has occurred in Jerseys. The heterozygous form in Dexters is easily recognized by the shortness of the limbs. The heterozygote in other breeds is normal in appearance.
Other types of dwarfs have been described and include ‘comprest’ and ‘compact’ cattle in Herefords and Shorthorns and various other forms of proportional dwarfs. For example, in Charolais, miniature calves that are exact replicas of normal calves but weigh only 5–16 kg at birth and are born 2 or more weeks prematurely, have been recorded. Most are dead at birth or die soon after so that the condition is effectively lethal. Proportional dwarfs occur also in Simmentals.
Other forms of chondrodystrophy, including ‘bulldog calves’ and one which causes fatal nasal obstruction in the German Black Spotted breed of cattle, have also been recorded. In the latter there are multiple deformities of limb bones and the condition appears to be inherited due to the influence of a single recessive gene.
Dwarf lambs occur sporadically. The best known is the mutant Ancon which has appeared and disappeared three times, with one incidence in New Zealand and one in the United Kingdom. The defect is chondrodysplasia and the lambs are not viable.
This inherited defect is recorded in Aberdeen Angus calves which are stillborn and undersized. The major manifestations are shortening of the mandible with protrusion of the tongue, impaction of the lower molars, a patent fontanelle, and the characteristic lesion of shortness of the long bones and absence of a marrow cavity in them. The absence of the marrow cavity, caused by defective remodeling of the bone, gives it a homogeneous shaft leading to the colloquial name of ‘marble bone’. Radiographic examination makes antemortem diagnosis simple. It is considered to be an autosomal recessive trait. It is reported also in foals but there is doubt about its genetic origin in that species.
This defect is inherited in Limousin cattle. The cranial bones are deformed so that the head resembles that of a sheep. The accompanying defects in heart, buccal cavity, tongue, and abomasum increase the chances of an early death.
Partial or complete absence of the mandibles with ventral displacement of the ears is common in sheep and is categorized as a lethal recessive because the sheep are unable to graze properly.
Inherited as a simple recessive character this defect usually results in the death of affected calves within the first week of life. The six premolars of the lower jaw are impacted or erupted in abnormal positions, often at grotesque angles. The mandible is shorter and narrower than normal. There is no abnormality of the incisors or upper jaw.
Defective apposition of upper and lower incisors, or lower incisors and dental pad in ruminants may result in inefficient grazing and malnutrition. Abnormal protrusion of the mandible (mandibular prognathism) is of most importance in ruminants and there is good evidence that abnormal length of the mandible is inherited. Amongst British breeds of cattle the defect is more common in beef than in dairy breeds. In Herefords and Angus the inheritance is thought to be conditioned by a single recessive gene.
Brachygnathia, underdevelopment of the mandible, has also been recorded in Dairy Shorthorn, Jersey, Holstein, Ayrshire, and Simmental cattle, with the defect so severe in some cases that the animals are unable to suck. In Angus brachygnathia can occur linked to a generalized degenerative joint disease, in which all joint surfaces are involved. Affected animals, detected at a few days to 4 months of age, are not viable.1 Inheritance of the defect is probably conditioned by a recessive gene.
A less severe degree of brachygnathia has been recorded in Merino and Rambouillet sheep. The mode of inheritance is suggested to be by the interaction of several pairs of genes.
Mandibular prognathism occurs as a part of other more general defects including achondroplastic dwarfism and inherited displaced molar teeth.
Brachygnathia is also seen in horses.2 The defect is present at birth but is often not apparent until much later.
The disease occurs in a number of pig breeds, but has been shown to be inherited only in Poland China pigs and their crossbreds. There is a deficit in the cranial bones and meningoceles or encephaloceles may result. The pigs are not viable. Genetic experiments have shown the inheritance to be of a recessive character with varying penetrance.
Many single cases of cranial and spinal deformity in farm animals have been likened to the human Arnold–Chiari malformation but a specific syndrome of protrusion of the medulla oblongata and the cerebellum through the foramen magnum into the spinal canal has not been identified in a hereditary context in these species.
The defect is incompatible with life. One form in Border Leicester lambs is characterized by a variable degree of nasomaxillary hypoplasia, often associated with incomplete cerebral development with less pronounced sulci and gyri than normal. It appears to be inherited in a simple autosomal recessive mode. A similar lethal defect is recorded in Angus cattle (as brachygnathia superior) in association with generalized degenerative joint disease.1
Cyclops anomaly occurs sporadically without known cause, but attracts attention when it is part of an inherited, prolonged gestation syndrome when it is often the cause of the investigation being mounted.
This suspected inherited disease of Simmental, Brown Swiss, Italian Brown calves,1 and other European breeds of cattle is manifested by excessively long, thin, distal extremities which give the calves a spidery look, hence arachnomelia. The bones are very fragile, there is curvature of the spine, foreshortening of the mandible, and associated cardiac and vascular defects. In Swiss Braunvieh cattle it is combined with arthrogryposis.2 It is thought to be inherited as a simple recessive.
A hereditary chondrodysplasia is recorded in Suffolk and Hampshire lambs3 in which the limbs are thin, disproportionately long, and have abnormal positions of the bones about the joints causing abnormalities of posture. There is also less muscle than normal. In severe cases the deformities are obvious at birth and may be lethal. In less severe cases the deformities do not become apparent until the lambs are several weeks old. The defects are readily visible in X-rays before clinical signs develop, and affected lambs can be detected in this way. The diagnostic lesion is multiple irregular islands of ossification in the upper limb joints.4 Spinal deformities, especially kyphoscoliosis, and cranial deformities including a roman nose, deviation of the nose poll axis, and shortening of the mandible are observed in some lambs. Inheritance by an autosomal recessive gene with complete penetrance and variable expressivity has been established as the cause in Suffolks.5 The defect is thought to be one of deficiency of an insulin-like growth factor (IGF) and IGF-binding proteins.6 Differentiation from arthrogryposis-hydranencephaly is important because of the superficial similarity of the two diseases.
A chondrodysplasia resulting in a dwarfing phenotype has occurred in a Texel sheep flock as a newly recognized recessively inherited genetic disease of the Texel breed.7 Affected lambs appear normal at birth but show evidence of dwarfism, wide-based stance and exercise intolerance as early as 1 week of age. Death usually occurs within 3 months, often after developing bilateral varus deformity of the forelimbs. Some severely affected lambs die with respiratory distress, probably due to tracheal collapse. Gross and microscopic lesions of variable severity were present in the tracheal, articular, epiphyseal, and physeal cartilage. In severe cases, articular cartilage in major joints was eroded from weight-bearing surfaces. The trachea was flaccid, abnormally kinked, and had thickened cartilaginous rings and a narrow lumen. Affected sheep which survived to breeding age commonly developed severe degenerative joint disease. Histologically, chondrocyte were disorganized, surrounded by concentric rings of abnormal fibrillar material and the matrix often contained focal to coalescing areas of chondrolysis. The disease has considerable potential as a suitable model for studying various forms of therapy for human chondrodysplasia.
1 Testoni S, Gentile A. Vet Rec. 2004;155:372.
2 Konig H, et al. Tierärztl. Umschau. 1987;42:692-695.
3 Rook JS, et al. J Am Vet Med Assoc. 1988;193:713.
4 Vanek J, et al. J Am Vet Med Assoc. 1989;194:244.
5 Oberauer AM, et al. Small Rumin Res. 1996;18:179.
A lethal congenital defect of the axial skeleton of purebred Holstein calves has been reported in Denmark,1 the United States,2 and in the UK which are not carriers of the CVM gene.3,4 It is caused by a mutation in the gene SLC35A3 coding an uridine-diphosphate-N-acetylglucosamine transporter. A single-base transversion of guanine to thymine has been located in the abnormal allele at postion 559.5 It is present in both copies of the allele and the mutation is lethal. It is a simple recessive genetic defect which requires that both the sire and the dam of an affected calf are carriers.
Most affected calves are born between day 250 and 285 of gestation. Approximately 80% of homozygous affected fetuses are aborted before gestation day 260.6 Birth weights are reduced. Most affected calves are stillborn, but affected calves occasionally are born alive. Euthanasia must be performed for humanitarian reasons.
In premature, stillborn, and neonatal affected calves, the defect is characterized by congenital growth retardation, malformed vertebrae, and tetramelic arthrogryposis.1,5,7 There is shortening of the cervical and thoracic parts of the vertebral column due to multiple hemivertebrae, fused and misshaped vertebrae, and scoliosis. Growth retardation and vertebral malformation are typical lesions. Malformation of the head, primarily in the form of dysplasia or palatoschisis, also occurs.
Symmetrical flexures of the carpal and joints and the metacarpophalangeal joint in combination with a slight lateral rotation of the phalanges are also present. Similar low-grade arthrogryposis are present in the pelvic limbs. Heart defects were present in 50% of affected calves (interventricular septal defects, dextroposition of the aorta, and eccentric hypertrophy of the right ventricle).1
Retrospective genotyping of affected calves according to the mutation in the SLC35A3 gene, and there were homozygous affected, heterozygotes, and homozygous normal.5 The morphological expression of the malformation is wide but certain aspects such as growth retardation, vertebral malformation, and symmetrical arthrogryposis are almost constant findings. A presumptive diagnosis of the malformation can be made in most cases based on necropsy findings combined with pedigree analysis and genotyping.5 Breeding studies were carried out in Denmark using selected cows that were progeny of sires with a heterozygous genotype for the malformation, and were pregnant after insemination with semen from another sire with heterozygous malformation genotype. The number of calves born with the malformation was less than expected suggesting increased intrauterine mortality.7 Fertility traits in Holsteins are severely affected by the malformation phenotype of the fetus.6 If the fetus is homozygous for the malformation, 29% of the cows will abort before gestation day 100 increasing to 45% at day 150, and 77% at day 260. Non-return to service rates, frequency of calvings after the first insemination, and interval from insemination to next calving were significantly reduced by a fetal malformation phenotype.
Pedigree analysis and DNA analyses of semen from sires used for insemination have found a widely branched familial occurrence of the malformation in the Holstein breed.5 The mutation in the SCL35A3 gene has been traced to the US sire Penstate Ivanhoe Star born in 1963 and his widely used son Carlin-M Invanhoe Bell born in 1974. The malformation mutation is not restricted to descendants of the American Holstein Friesian bull-Carlin-M Ivanhoe Bell. Through these sires and elite sires genetically related to them, the defect has been disseminated in the Holstein breed worldwide. Using a hair root sample from the dam of the calf, a DNA test is available. Testing is available on registered or registerable Holstein animals only through the Holstein Association (Holstein USA) or through one of the National Association of Animal Breeders’ member AI organizations or at the Van Haeringen Laboratorium, Wageningen, The Netherlands. A PCR test is being developed.8
1 Agerholm JS, et al. J Vet Diagn Invest. 2001;13:283.
2 Duncan RBJr, et al. J Vet Diagn Invest. 2001;13:333.
3 Johnson VS, et al. Vet Rec. 2003;153:598.
4 Revell S. Vet Rec. 2001;149:659.
5 Nielsen US, et al. Livestock Prod Sci. 2003;79:223.
6 Agerholm JS, et al. J Vet Diagn Invest. 2004;16:548.
Patients affected by this deformity, e.g. ‘mole’ calves of the Danish Black and White breed, are characterized by shortened and malformed limbs, especially the extremities which are sometimes missing altogether. In male calves there is also hydrocephalus, hypoplasia of the mandible, and absence of part of the face. The body is edematous. Many are aborted during the latter part of pregnancy. The deformity is conditioned by a single recessive gene.
This defect has been recorded in cattle and appears to be inherited as a single recessive character. The limbs are normal down to the metacarpal and metatarsal bones, which are shorter than usual, but the first two phalanges are missing and the normal hooves and third phalanges are connected to the rest of the limb by soft tissues only. The calves are unable to stand but can crawl about on their knees and hocks.
Bilateral absence of the distal half of the limb, e.g. the patella, and shortening or absence of the tibia, often accompanied by hydrocephalus, meningoceles, ventral abdominal hernia, and cryptorchidism, comprise the syndrome known as tibial hemimelia. It is inherited in the Galloway breed of cattle. An autosomal recessive mode of inheritance is assumed. A concerted program of eradicating the defect has been undertaken, based on test matings and examination for defects of 90-days fetuses obtained by terminating pregnancy with prostaglandin.
Hereditary peromelia of mohair goats.
This syndrome includes agenesis of the phalanges and parts of the metacarpus and metatarsus affecting one or more limbs, and an autosomal recessive mode of inheritance.1,2
An even more serious defect, in which the mandible and all the bones below the humerus and stifle are vestigial or absent, has been reported in British, French, and German Friesians. It appears to be conditioned by the inheritance of a single recessive gene. Similar ‘amputates’ have been shown not to be inherited.
Extra claws (polydactylism) and fusion of the claws (syndactylism) are known hereditary defects of cattle, the former in the Normandy breed and the latter in Holsteins,1 Angus, Hereford, and Chianina.
Dactylomegaly (enlarged dew claws), often associated with syndactyly or deviation of the adjacent major digit and creating a clubfooted appearance, may be inherited in Shorthorn cattle. In most cases they cause no more than inconvenience but an association of syndactyly with susceptibility to hyperthermia is recorded, and some of these animals die of hyperthermia when subjected to high environmental temperatures.
Adactyly is a recorded but less well defined defect in cattle and sheep in which the hooves are absent at birth.
There is good field evidence that corkscrew claw or curled toe is an inherited defect in cattle, especially in beef breeds, but also in Holstein-Friesians. It is almost always the lateral claw which is affected; in some breeds it is more common in the hind feet, and in others it is more common in the front feet. In the affected digit the third phalanx is much smaller than normal and is narrower and longer. The soft tissue and the horn are correspondingly deformed so that the horn grows much longer and narrower and tends to curl over the sole so that the cow walks on the wall of the hoof. The claw also curls over the front of the other digit of the limb. There are often cracks in the front of the claw, originating at the coronet and causing serious lameness. All affected animals suffer gait abnormalities as they get older and heavier. Much of this is due to distortion and wear of the articular surfaces in the companion claw which has to carry much more weight than is usual. Marked changes in the affected digit are detectable by anteroposterior radiography.2
Multiple exostosis affecting both cortical and medullary bone of the limbs and ribs has been described in Quarter horses and Thoroughbreds in the US. The lesions are visible externally but cause little apparent inconvenience. It is inherited as a single dominant autosomal gene. Restriction nuclease analysis is used to diagnose the disease.1
This defect is thought to be caused by the inheritance of a simple recessive character. Affected piglets show obvious lesions at birth and, although many of them die or are destroyed immediately, a proportion of them may survive. The forelimbs are markedly enlarged below the elbows and the skin is tense and may be discolored. There is difficulty in standing and moving about, and starvation and crushing contribute to the mortality rate. There is extensive edema of the subcutaneous tissues, thickening of the bones, and roughness of the periosteum. It is thought that the primary lesion is a separation of the periosteum from the bone.
This disease of pigs is indistinguishable from rickets due to nutritional inadequacy. The pigs are healthy at birth. Subsequently there is hypocalcemia, hyperphosphatemia, and increased serum alkaline phosphatase. The defect is a failure of active transport of calcium through the wall of the small intestine.
Complete absence of the tail or deformity of the appendage occur relatively commonly as a congenital defect. The condition is thought to be inherited in Holstein cattle and in Landrace and Large White pigs. It is often seen in combination with other deformities of the hindquarters such as atresia ani and urogenital tract abnormalities.
Inherited fixation of limb joints present at birth is recorded in many breeds of cattle especially in the Shorthorn, Charolais, Piedmont, and Swedish Dole. It is thought to be inherited as a single recessive character. There are many environmental causes of the disease, the most common of which is Akabane virus infection of early pregnancy and discussed under that heading.
The limbs of affected calves are fixed in flexion or extension and cause dystocia due to abnormal positioning and lack of flexibility. There is no involvement of joint surfaces and the joints can be freed by cutting the surrounding tendons or muscles. There is atrophy of limb muscles and those calves which are born alive are unable to stand and usually die or are destroyed within a few days.
This defect in cattle appears to be inherited in a dominant manner. The teeth are soft, fleshy, and easy to bend. There is no defect of bones or joints other than marked softness and the presence of excess cartilage at the epiphyses. There is abnormal ossification of the cartilage. The calves are of normal size, do not cause dystocia, and, although they are unable to stand because of the excessive flexibility of the limbs, they can suck. Hypostatic pneumonia usually develops and causes death of the calf.
This is inherited as a simple recessive with low penetrance in pure French Charolais in France and high penetrance in 7/8 Charolais cattle in Canada, where the gene frequency is high in purebred and crossbred Charolais. Among crossbred Charolais cattle the homozygous condition is almost always markedly expressed and lethal, but a high percentage of purebred homozygous cattle show slight to no visible effect of the gene and survive. Because of the low rate of prevalence in France, attempted eradication does not appear to be economical.
In this syndrome all limbs are usually affected but the front limbs more than the hindlimbs, and the more distal joints are more rigidly fixed than proximal ones. The muscles of affected limbs are atrophic and pale in color. Histological changes in the spinal cord suggest that the muscle atrophy is neurogenic. In affected calves the gestation period may be longer than normal by an average of 2 weeks.
In Simmentals a combined set of defects includes arthrogryposis, often with the limbs in a wraparound position around the body, underdevelopment of the mandible, curvature of the spine, and defects of the heart and main vessels.
Inherited arthrogryposis has also been recorded in Merino and Corriedale sheep, and in Norwegian Landrace pigs in which it is thought to be inherited as a simple recessive. The Corriedale defect is associated with other lesions including brachygnathia inferior, hydranencephaly, and thoracic scoliosis. Inherited arthrogryposis in pedigree Suffolk lambs has been described.1 Breeding studies using superovulation and embryo transfer were used to increase the numbers of offspring from females which were carrying the gene or genes responsible for the defect which was inherited as an autosomal recessive trait.
An inherited arthrogryposis also occurs in Norwegian Fjord horses. The arthrogryposis affects the hindlimbs and there are accompanying defects of polydactyly, palatoschisis, and brachygnathia in some. Most foals are unable to stand and the defect must be considered to be a lethal one.
Multiple ankylosis affecting all limb joints has been recorded as an inherited congenital defect of Holstein calves. The abdomen of the dam shows marked enlargement at the 6th to 7th month of pregnancy and this may occasion some respiratory distress. Excessive fetal fluids are present and insertion of the hand per rectum is impeded by the distended uterus. Abortion during the last month of pregnancy is a common occurrence. Affected fetuses have a very short neck, ankylosed intervertebral joints, and varying degrees of ankylosis of all limb joints. The limbs are fixed in flexion and there is some curvature of the spine. Fetal dystocia always occurs and embryotomy or cesarean section is necessary to deliver the calf.
Ankylosis of limb joints combined with cleft palate occurs occasionally in Charolais cattle and is suspected of being inherited. Ankylosis of the coffin joint, developing at several weeks of age, has been reported in Simmental calves. The etiology of the condition is not clear.
Unilateral or bilateral subluxation occurs as an inherited defect in Bos indicus cattle and in water buffalo (Bubalus bubalis). Shetland ponies also have a predisposition and a monogenic autosomal recessive transmission is suspected.1,2 There is periodic lameness with the affected limb held in rigid extension; the patella is displaced medially. If the animal shakes the limb the patella may go back into its normal position and the problem is relieved.
This inherited disease is recorded only in Jersey cattle. It has assumed great importance because of the great popularity of a sire which carried the gene. There is abnormal flexure and extension of all joints but especially the hock, stifle, hip, knee, elbow, and shoulder joints. The muscles are much atrophied and the joints look very enlarged as a result. It is impossible for the calves to stand but they are bright, alert, and eat well. The limbs are so flexible that they can be bent into extraordinary positions, and almost tied in knots. A drawer sign, a displacement of the articular surfaces laterally, and produced by manual pressure, can be elicited easily and with a displacement of up to 2 cm. There are no detectable lesions in the nervous or musculoskeletal systems. Although the disease is known to be inherited as a simple autosomal recessive, it has also been seen in circumstances which preclude inheritance being the cause.
An inherited defective development of the acetabulum occurs in Dole horses. There is no clinical evidence of the disease at birth but osteoarthritis of the joint and disruption of the round ligament develop subsequently. For this disease in cattle see ‘Degenerative joint disease’.
Generalized glycogenosis is a glycogen storage disease of Corriedale sheep,1 Shorthorn, and Brahman beef cattle which resembles Pompe’s disease in humans.2,3 Glycogenosis type II in Shorthorn and Brahman cattle is a lysosomal storage disease in which acidic α-glucosidase is the defective enzyme. In Shorthorn cattle, glycogenosis type II is caused by a single mutation, but the initial DNA/PCR restriction enzyme test of amplicons, was occasionally compromised by inhibition of the restriction enzyme by undefined factors. This was overcome by introduction of wild and mutant allele-specific amplifications and the use of two restriction enzymes, which clarified the anomalies and provided a more accurate testing system.2
In Brahman cattle, glycogenosis type II is associated with loss-of-function alleles affecting the α-glucosidase gene that differ from that in Shorthorns. There is a common mutation affecting many Australian Brahmans and a less common one affecting descendants of one imported bull. In addition, a third mutation was associated with significantly reduced α-glucosidase activity, but not sufficient to cause clinical disease in the homozygous state.3
Clinical signs include poor growth, muscle weakness, incoordination of gait, and difficulty in rising. The animals become permanently recumbent. The disease is identified as a lysosomal storage disease with lesions present in skeletal and cardiac muscle, and central nervous tissue. During the course of the disease there is progressive muscular damage and acute degeneration of muscle fibers in the terminal stage. Affected Brahman calves die at 8–9 months of age and British breed cattle at over 1 year. Only histopathological lesions are evident and include extensive vacuolation and accumulations of granular material in affected tissues. Amongst the biochemical lesions are greatly diminished α-glucosidase activity in liver and muscle, and a correspondingly high level of glycogen. Animals in affected herds are divisible into normal heterozygotes and homozygotes on the basis of α-1,4-glucosidase activity in lymphocytes or in muscle, especially the semitendinosus muscle.
Genotyping methods using hair root and blood samples to test Shorthorn cattle for generalized glycogenosis are available,2 and PCR assays have been developed to genotype Brahman cattle for loss-of-function alleles within the acidic α-glucosidase gene.3
Glycogen storage disease Type V is one of a number of inherited diseases affecting glycogen metabolism and resulting in abnormal accumulation of glycogen in cells. Glycogen storage disease Type V has been recorded in Charolais cattle in North America.1 As in Type II glycogenosis, Type V is inherited as an autosomal recessive trait α-glucosidase. There is a deficiency of myophosphorylase, mildly elevated muscle glycogen and elevated serum creatine and aspartate aminotransferase. Severely affected animals may develop rhabdomyolysis which may be accompanied by myoglobinuria.2
In Charolais cattle, glycogen storage disease Type V is usually seen in calves at several weeks or months of age and is associated with exercise. Calves lag behind their dam or herd and may become temporarily recumbent for several minutes; with continuous exercise there are further periods of collapse and recumbency which may become prolonged. Not all homozygous animals are clinically affected if they are allowed to ‘pace their exercise’ and some animals have been known to breed despite muscle weakness.
A polymerase chain reaction-restriction fragment length polymorphism test has been used to identify heterozygous individuals in a Charolais herd in New Zealand that were otherwise normal.2 Using a similar test, a Blonde d’Acquitaine cross-bred calf with a double-muscled phenotype and suspected of having myophosphorylase deficiency based on clinical findings of brown-colored transparent urine after exercise, pain, and an elevated creatine kinase was considered negative.3
This myopathy is associated with exertional rhabdomyolysis and occurs with a high incidence in some Quarter Horse, American Paint, Appaloosa, and Quarter Horse cross-bred families. An autosomal recessive pattern of inheritance is proposed.4 Recurrent episodes occur at intervals of about 2 weeks. Clinical signs include exercise intolerance with prolonged recumbency in some. Discomfort varies between stiffness and pain suggestive of colic. Myoglobinuria is common during episodes of clinical illness. Serum activity of creatine kinase are elevated. Biopsy of gluteal or semitendinosus muscles reveals polysaccharide inclusion bodies in some muscle fibers and widespread sarcolemmal vacuoles. The defect is basically an error of glycolysis.
This is an inherited defect in diaphragmatic muscle of Meuse-Rhine-Yssel and Holstein-Friesian cattle1 appearing in adults and characterized by anorexia, decreased rumination, and eructation leading to recurrent bloat, dyspnea, abdominal respiration, nostril dilation, and death from asphyxia after a course of several weeks. Necropsy lesions comprise degenerative changes in diaphragmatic and thoracic muscles. The immunochemical evaluation of some cytoskeletal proteins of affected muscles found an increase in the amount of desmin and vinmentin immunoreactivities and similar amounts of actin and α-actin compared with controls.2
Congenital myasthenic syndrome has been reported in Brahman cattle in South Africa.1 Affected calves develop progressive muscular weakness, beginning at birth and up to 3–4 weeks of age. Within 1 week they are unable to stand without assistance. Some calves are able to stand and walk for 30 to 45 minutes before collapsing, but are still able to suck their dams. The calves remain alert and continue sucking but may collapse after 20 to 60 seconds. The weakness becomes progressively worse and affected calves are usually euthanized. Hematology and serum biochemistry are normal, and muscle biopsies do not reveal any abnormalities.
The underlying defect is a homozygous 20-base pair (bp) deletion in the gene, muscular acetylcholine receptor (bovCHRNE), coding for the -subunit of the nAChR at the neuromuscular junction.2 A PCR-based DNA test, using blood or semen has been developed and validated.3 The test makes it possible to differentiate rapidly and accurately between homozygous wild-type, heterozygous and homozygous affected animals. Preliminary testing of Brahman cattle in South Africa revealed several carrier animals, some of them influential in the breeding population.
This disease has been reported occurring in Gelbveih cattle in several separate beef herds in the United States.1 Affected animals are 4 to 20 months of age, and the mortality rate is 100%. Clinical findings include ataxia, weakness, and terminal recumbency. Gross and histological muscle lesions were indicative of nutritional muscular dystrophy with no myocardial lesions. Acute to chronic lesions in most large skeletal muscle groups consist of degeneration, necrosis, regeneration, fibrosis, and atrophy. Fibrinoid necrosis of arterioles is a common feature in multiple tissues. Lesions in the spinal cord white matter and peripheral nerves consisted of degeneration of the dorsal columns and axons, respectively. Chronic interstitial nephritis with fibrosis, hyaline droplet change, and tubular epithelial vacuolar change were most severe in older calves. Vitamin E levels were deficient in most affected calves. Pedigree analysis found a common ancestry for all but one of the affected calves. It is hypothesized that a hereditary metabolic defect, possibly involving anti-oxidant metabolism may be the causative factor.
Umbilical hernias in cattle and scrotal hernias and cryptorchidism in pigs have been considered to be inherited defects for many years but the evidence is uncertain.
Umbilical hernias are commonly identified in dairy heifers. In 18 commercial dairy herds in New York, 15% of heifer calves had umbilical hernias during the first 3 months of age.1 The economic costs of umbilical hernias include the cost of medical and surgical treatment and the loss in value for breeding animals.
It has been generally accepted that umbilical hernias may be inherited in a dominant or recessive mode. Some studies have found the risk of hernias was higher in some breeds: the incidence being much higher in Holstein cattle than other breeds such as Angus, Ayrshire, Brown Swiss, Charolais, Guernsey, Hereford, Jersey, and Shorthorn. However, factors other than genetic may be important. For example, many veterinarians have observed that umbilical infections commonly lead to umbilical hernia by slowing closure of the umbilicus. It is unlikely that the responsible genes are sex-linked, in spite of the apparent greater incidence in females. Umbilical hernias in Holstein-Friesian cattle can also be conditioned by a dominant character with incomplete penetrance, or be due to environmental factors. In a case control study to determine risk factors associated with identification of an umbilical hernia during the first 2 months after birth in Holstein heifers, the sire and umbilical infection were associated with risk of a hernia.2 Heifers born to sires with = 3 progeny with an umbilical hernia were 2.31 times as likely to develop a hernia as were heifers born to sires with = 2 progeny with an umbilical hernia. Heifers with umbilical infection were 5.65 times as likely to develop a hernia as were heifers without umbilical infection. Attributable proportion analysis found that the frequency of umbilical hernias in Holstein heifers with umbilical infection would have been reduced by 82% if umbilical infection had been prevented.3
The risk factors for congenital umbilical hernias in German Fleckvieh calves offered for sale at livestock markets were examined.4,5 An umbilical hernia was defined as a palpable opening in the abdominal wall of the umbilical region >1.5 cm, even if no hernia had developed. Inflammation, abscesses or fistulae were excluded. Data from 53 105 calves were collected from 77 livestock markets over a 2-year period. The overall incidence of congenital hernia was 1.8%. The analyses found significant effects for sex of calf, birth type, age of calf at examination, market place and date, sire line, sire, and frequency of affected herdmate calves in male calves, the incidence was 2.2%, in females 1.5%. The calves varied from 3 to 8 weeks of age. The diameter of hernial openings was between 1.5 and 9 cm with 47% of affected calves with a hernia measuring greater than 3 cm. A significantly higher incidence occurred in twin or triplet calves. Shorter gestation periods increased the risk of hernias linearly by a factor of 1.3% for 10 days. There were differences in the incidence of hernias according to sire lines but the heritabilty estimates were low varying from h2 = 0.04 (>100 progeny) or h2 = 0.05 (>25 or 50 progeny). However, analysis of the data found no evidence for an autosomal monogenic recessive inheritance. The analyses indicated that the incidence of congenital umbilical hernia observed could not be explained by one autosomal recessive gene locus, but it seemed much more likely that more than one gene locus is involved or a mixed multifactorial monogenic mode of inheritance may be the underlying genetic mechanism. It is suggested that the incidence of congenital umbilical hernias could be reduced if all breeding bulls are examined as calves and a veterinary certificate confirms a closed umbilical ring.
Breeders should be aware of the implications of congenital hernias and thus, congenital hernia should get more attention in the selection process of young sires.
Breeding studies and genotyping using the Canadian Holstein bull ‘Glenhapton Enhancer’, have provided evidence that Enhancer is the carrier of major dominant or codominant gene with partial penetrance for umbilical hernia.3 Five sons of Enhancer produced progeny with >10% frequency of umbilical hernia, whereas the progeny of 3 sons had <3% umbilical hernia. Genotyping of grand-progeny found significant differences in paternal allele frequencies between the affected and unaffected progeny groups for a marker BMS1591 on bovine chromosome 8(BTA8). The umbilical hernia-associated paternal allele originated from Enhancer.
Scrotal hernias of pigs have also been shown to be inherited in some breeds, e.g. Duroc and Landrace, but not in others, e.g. Yorkshires.6
This is an inherited condition, characterized by an increased bulk of skeletal muscles due to the presence of a greater than normal number of muscle fibers; it is well known in many breeds of cattle but appears to be most common in the Charolais, Belgian Blue, Piedmont, and South Devon breeds. The condition is recorded only rarely in sheep. The mode of inheritance has not been established but heterozygotes usually show some degree of muscle hypertrophy. Many of the muscle changes are in the direction of the current demand for lean, meaty carcasses, and there is interest, especially in Europe, in the exploitation of this anomaly for meat production. Pietrain pigs (see below) exhibit many of the characteristics of double-muscled cattle, including large muscle mass and susceptibility to stress.
Severely affected cattle show a marked increase in muscle mass most readily observed in the hindquarters, loin, and shoulder, an increase in the muscle:bone ratio and a decrease in body fat. Affected calves demonstrate above-average weight gains during the first year of life if well fed and managed, although mature size is somewhat reduced. Well-marked grooves along the intramuscular septa in the hindquarters are a distinguishing feature as is an apparent forward positioning of the tail head. Macroglossia, prognathism, and a tendency toward muscular dystrophy and rickets have been observed in affected calves. Electrocardiographic abnormalities have been reported.1 The condition often gives rise to dystocia, possibly due to increased gestation length, and affected females are said to be less fertile than normal.2 There is also a very high incidence of Elso heel in affected cattle and this interferes greatly with their economic value. Other associated defects are brachygnathia and deviation of the incisor arch and, in Belgian Blue and White cattle, greater susceptibility than normal to laryngitis and bronchopneumonia.3
A progressive muscular weakness is found in stress-susceptible Pietrain pigs. The syndrome commences with muscle tremor at 2–4 weeks of age, leading to complete recumbency by 12 weeks of age. At this stage the pigs move with a creeping gait with the limbs flexed. There are no neuropathological lesions but there are myopathic changes, especially in the forelimbs.
This is a primary skeletal muscle disease of sheep with a strong probability of having a genetic mode of transmission.1 It is recorded in Merino flocks in Australia and is characterized by a gradually progressive failure to flex the joints of the hindlimbs commencing at 3–4 weeks of age. Eventually the limbs are rigid at all times, and running becomes impossible. The forelimbs and the head and neck are normal. Affected sheep are easily detected when they are 1 year old and will have mobility problems by the time they are 2–3 years old. At necropsy there are pale areas in skeletal muscle and sometimes the muscles of the diaphragm in those sheep which have a tendency to bloat. The histopathology and histochemistry of the muscle lesions is comparable with that of inherited muscle atrophies in humans.1,2
A progressive ataxia, weakness, muscle atrophy, and recumbency develops in young calves, mostly during the first 2 weeks of life. Sensory functions are unimpaired. Some are already affected at birth and some may be stillborn. No new cases occur after 3 months of age. Conditioned by an autosomal recessive gene the defect occurs in Red Danish cattle which originated from Brown Swiss, and from German Braunvieh and American Brown Swiss. The primary lesion is degeneration of ventral horn cells of the spinal cord, without involvement of the brainstem or cerebellum. The visible lesion is the secondary atrophy of the denervated muscles.1,2
Recorded only in Jersey cattle, this defect appears to be conditioned by an inherited gene; probably a monogenic autosomal recessive. Lameness becomes apparent at 2–4 months of age, the toes becoming increasingly widely spread and the toes themselves misshapen. Walking and standing are painful, especially on the front feet so that some animals graze and walk on their knees. Affected animals either lie down increasingly or stay standing for very long periods. The apparent abnormality is a defect of the muscles and ligaments holding the phalanges together.
Etiology Defect in sodium channel of skeletal muscle.
Epidemiology Disease of Quarter Horses and crossbreds. Inherited as an autosomal dominant trait with variable penetrance.
Clinical signs Episodes of muscle fasciculation, stridor, muscle weakness, and flaccid paralysis.
Clinical pathology Hyperkalemia during episodes. Gene probe to detect mutated gene.
Treatment Palliative. Potassium-free intravenous fluids. Acetazolamide.
The disease is caused by a heritable defect in the sodium channel of skeletal muscle.1 The mutation, of which only one form has been identified, results in substitution of a cytosine for guanine, with consequent replacement of phenylalanine by leucine in a transmembrane protein regulating sodium flux across the cell membrane and T-tubule. The disease is transmitted as an autosomal codominant with the result that homozygotes are more severely afected than heterozygotes, and phenotypic expression (disease severity) differs among heterozygotes.
The disease is familial and affects Quarter Horse and crossbred descendants of a single Quarter Horse sire, Impressive.2,3 More than 50 000 registered Quarter Horses are related to known carriers of the disease.4 Quarter Horses with the disease are presumably selected because they outperform unaffected animals in the halter classes in which they compete at horse shows,5 although recent rule changes have changed this practice. The disease is occurs in breeds derived from or crossed with Quarter horses including Appaloosas, American Paint horses, and crossbreds.
The disease is inherited in an autosomal codominant manner.1 Therefore, 50% of the offspring of the breeding of a heterozygote and a normal animal will carry the trait, as will 75% of the offspring of the breeding of two heterozygotes. Of the breeding of 2 heterozygotes, 50% of progeny will be heterozygotes, 25% homozygotes for the mutated gene, and 25% homozygotes for the normal gene. Animals homozygous for the abnormal gene are uncommon, representing only 0.9% of animals tested for the disease.6 The low prevalence of the homozygote genotype is likely a reflection of severity of disease and the reduced likelihood that homozygotic animals will reach sexual maturity.
The risk of a heterozygous animal being affected with periodic paralysis is variable. Most heterozygous horses appear normal and never experience an attack, while others have severe episodes starting at a young age. Homozygous horses are much more likely to have severe manifestations of the disease at a young age.
The abnormality in the sodium channel coded for by the mutated gene predisposes the horse to episodes of complete depolarization of the muscle membrane and flaccid paralysis. The mutation in the sodium channel increases the probability that any one channel is open, with the result that the resting membrane potential in affected horses is higher (less negative and closer to the depolarization threshold) than that of normal horses.7 This results in fre-quent depolarizations of individual muscle fibers causing muscle fasciculations. The weakness associated with severe episodes of the disease results from failure of sodium channels to close after depolarizations. Opening of potassium channels when the muscle is depolarized results in movement of potassium out of the muscle cell, and the development of hyperkalemia.
The disease in heterozygous animals is characterized by periods of muscle fasciculation and tremor that progress to weakness, paralysis, and recumbency. Such episodes may last minutes to hours, and most resolve spontaneously. Horses often sweat, have prolapse of the third eyelid, and contraction of facial and locomotor muscles during episodes. Episodes may be mistaken for colic. Inspiratory stertor commonly noted during episodes is probably due to laryngeal and pharyngeal dysfunction.
Episodes are more frequent and severe in homozygous animals and signs of laryngeal and pharyngeal dysfunction, such as stridor and dysphagia, occur in almost all of these animals.6,8 Endoscopic examination of homozygotes reveals pharyngeal collapse, laryngopalatal dislocation, and laryngeal paralysis.6,8 The disease can manifest in foals as young as 7 days of age. The severity of signs in some homozygotes diminishes with age.
Electromyographic demonstration of myotonic discharges, prolonged insertional activity, and doublets and triplets is a sensitive and specific indicator of the disease.9
Horses with HYPP have reduced exercise tolerance compared to normal horses.10 Homozygotic horses have laryngospasm, airway obstruction, hypoxia, hypercapnia, and ventricular depolarizations during intense exercise, which is not recommended for these horses.11
Hyperkalemia (>5.5 mEq/L, 5.5 mmol/L) during or immediately after episodes is characteristic of the disease, although the existence of a normokalemic variant has been suggested.12
Diagnostic confirmation has in the past been achieved by provocative testing by administering potassium chloride (88–166 mg/kg, orally) to suspect horses.13 However, the development of genotyping has rendered provocative testing obsolete and, for humane reasons and because of the risk of death, its use is not recommended. The test of choice for demonstrating the presence of the mutated gene is a specific gene probe.4 The probe can be applied to various tissues, but blood or hair, with attached root (a plucked hair), are preferred for diagnostic testing of live animals. This test classifies horses as normal, heterozygous, or homozygous but does not indicate the propensity of heterozygotes to exhibit the disease. Samples can be analyzed in the United States at the Veterinary Genetics Laboratory, University of California (www.vgl.ucdavis.edu).
Most acute episodes resolve spontaneously or with only minor treatment. The aim in treating more severe or prolonged episodes is to reduce the plasma potassium concentration by intravenous infusion of isotonic, potassium free fluids such as sodium chloride, sodium bicarbonate, or dextrose. Some authors recommend infusion of calcium gluconate but others caution against its use. A practical approach is the slow intravenous administration of 0.25 to 0.5 mL of 23% calcium gluconate per kg of body weight (125–250 mL for a 500 kg horse) diluted in isotonic sodium chloride or, preferably, 5% dextrose. Administration of NaHCO3 at 1 mL/kg intravenously has been suggested.
Maintaining affected horses on a low potassium diet reduces the frequency with which episodes occur. Alfalfa (lucerne), some oils including soyabean, molasses, lite salt (a mixture of KCl and NaCl), and many sweet feeds are potassium rich and should be avoided. Grass hay (timothy) and straw and oats, corn, and barley are low in potassium. There are commercial feeds that have a guarranteed low concentration of potassium. Alternatively, diets can be formulated using feed of known potassium concentration, as determined by feed analysis. Care should be taken that diets are nutritious and contain appropriate concentrations and ratios of calcium and phosphorus.
Acetazolamide (2–4 g/kg, every 12 hours) reduces the severity and frequency of episodes and is widely used to control the disease. The drug is poorly absorbed in horses but the concentration required in plasma of horses to achieve a pharmacodynamic effect is lower than that of humans.14
1 Rudolph JA, et al. Nature Gen. 1992;2:144.
2 Bowling AT, et al. Anim Gen. 1996;27:279.
3 Naylor JM, et al. J Am Vet Med Assoc. 1992;200:340.
4 Spier SJ. J Equine Vet Sci. 1993;13:140.
5 Naylor JM. J Am Vet Med Assoc. 1994;204:926.
6 Carr EA, et al. J Am Vet Med Assoc. 1996;209:798.
7 Hanna WJ, et al. J Physiol. 1996;497:349.
8 Traub-Dargatz JL, et al. J Am Vet Med Assoc. 1992;201:85.
9 Naylor JM, et al. Can J Vet Res. 1990;54:495.
10 Steele D, Naylor JM. Equine Vet Sci. 1996;202:933.
11 Maxson-Sage A, et al. Am J Vet Res. 1998;59:615.
12 Stewart RH, et al. J Am Vet Med Assoc. 1993;203:421.
Recurrent exertional rhabdomyolysis of Thoroughbred horses is a common disease characterized by repeated episodes of muscle disease. A similar disease occurs in Standardbred horses but its etiology and epidemiology are not well documented.
Recurrent exertional rhabdomyolysis in Thoroughbred race horses is inherited as an autosomal dominant trait with variable expression influenced by temperament, diet, and sex.1,2 Horses with recurrent exertional rhabdomyolysis have abnormal muscle contraction and a defect in myoplasmic calcium regulation.3,4 These abnormalities are evident after caffeine or halothane challenge of muscle fibers from affected horses examined in vitro.2-4 Myotubules from affected horses have higher concentrations of calcium after caffeine stimulation and muscle fibers from affected horses are more likely to contract when exposed to low concentrations of caffeine.3 The defect does not resemble that found in the ryanodine receptor in animals with malignant hyperthermia, and there is no defect in calcium-ATPase activity or its affinity for calcium in the sarcoplasmic reticulum of Thoroughbred horses with recurrent exertional rhabdomyolysis.5
A genetic basis to a similar disease in Standardbreds is suspected, based on analysis of pedigree information of trotters in Sweden.6
Interpretation of reports of prevalence and risk factors for exertional rhabdomyolysis is difficult because studies to date have mostly not differentiated between the recurrent exertional rhabdomyolysis of Thoroughbreds, polysaccharide storage myopathy of Quarterhorses and related breeds, and the sporadic disease in other breeds.
The incidence or 1-year-period prevalence of exertional rhabdomyolysis in Thoroughbreds is 4.9–6.7% in Thoroughbred racehorses in the United States, Australia, and Great Britain, and 6.1% in National Hunt Thoroughbreds in Great Britain.7-10 The disease occurs repeatedly in 74% of affected Thoroughbred race horses in Great Britain.10
Risk factors for exertional rhabdomyolysis in Thoroughbred horses, not all of which have the familial disease, include exercise, diet, use, and sex. Horses used for racing are more likely to have episodes of the disease than are horses used for pleasure riding or ‘other’ uses,7 although racing and breed (Thoroughbred or Standardbred) are confounding factors. Female race horses are three times more likely to have episodes of exertional rhabdomyolysis than are male (intact or castrated) race horses,7-10 and young, female Thoroughbreds are at greatest risk.7-10 Among National Hunt horses in Great Britain, females are 24 times as likely to have an episode of the disease as are males.9 Female polo ponies are not more likely to develop the disease.11 Thoroughbred racehorses and polo ponies, but not National Hunt horses, with a nervous or ‘flighty’ temperament are more likely to experience episodes of the disease.8,12,13 Other apparent risk factors include a rest day before hard exercise,8 feeding >4.5 kg of grain per day,8 lameness,8 and training gallops of shorter distance.9 Susceptible horses consuming a high calorie diet (>30 mCal/day) with a large proportion of the calories provided by readily digestible carbohydrate, such as starch, are at increased risk of the disease.14,15
The disease is of considerable economic impact because of its frequent occurrence in athletic horses, recurrent nature, and need to rest affected horses. On average, affected Thoroughbred race horses cannot train for 6 days after an episode, and approximately two-thirds of affected horses are unable to race because of the disease.9,10 The effect of the loss of training days for each episode is magnified because of the recurrent nature of the disease in a large proportion of affected horses. Approximately 6% of the wastage of Thoroughbred race horses in Australia is attributable to exertional rhabdomyolysis,16 though it is not known if all of these horses are affected by recurrent exertional rhabdomyolysis.
The underlying cause is described above under ‘Etiology’. The disease is due to dysfunction and death of myocytes with subsequent release of cellular constituents, including the enzymes creatine kinase, aspartate aminotransferase and carbonic annhydrase, and myoglobin. Cell death is likely linked to abnormal accumulation of calcium in intracellular fluids secondary to deranged energy and/or membrane function.17 Necrosis of myocytes caused pain and inflammation in the muscle, with infiltration of inflammatory cells. Healing and regeneration of myocytes occurs over a period of weeks in the absence of further episodes of myonecrosis.
The release of cellular constituents results in electrolyte abnormalities, primarily hypochloremic metabolic alkalosis, systemic inflammatory response, and pigmenturia. Severely affected horses can have a metabolic acidosis. Myoglobin and, possibly, other cell constituents are nephrotoxic and acute renal failure can develop as a result of myoglobinuric nephrosis. Pain and loss of muscle function are associated with stilted, short stepping gait.
The cardinal feature of the disease is the occurrence of multiple episodes of rhabdomyolysis following exercise of Thoroughbred horses. Clinical findings are variable and range from poor performance to recumbency and death. Signs are usually mild and resolve spontaneously within 1–6 days.
The usual presentation is a young (2–5-year-old) female racehorse with recurrent episodes of stiff gait after exercise. The horse does not perform to expectation and displays a short stepping gait that may be mistaken for lower leg lameness. The horse may be reluctant to move when placed in its stall, be apprehensive and anorexic, and frequently shift their weight. More severely affected horses may be unable to continue to exercise, have hard and painful muscles (usually gluteal muscles), sweat excessively, be apprehensive, refuse to walk, and be tachycardic and tachypneic. Affected horses may be hyperthermic. Signs consistent with abdominal pain are present in many severely affected horses. Deep red urine (myoglobinuria) occurs but is not a consistent finding. Severely affected horses may be recumbent.
Mildly or inapparently affected horses have moderate increases in serum creatine kinase (CK) (20 000–50 000 iu/L), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activity. Severely affected horses have large increases in CK (>100 000 iu/L) and other muscle-derived enzymes. Serum CK and AST activities peak approximately 5–6 and 24 hours after exercise, respectively11,18 and in the absence of further muscle damage serum AST might not return to normal levels for 7–10 days. The half-life of CK activity in serum is approximately 12 hours and in the absence of continuing muscle damage serum CK declines rapidly.11 The persistence of increased AST activity, compared to CK, is useful in identifying affected horses days or weeks after the episode.18
Serum myoglobin concentrations increase markedly during exercise in affected horses, and decline within 24–48 hours.18 Serum carbonic anhydrase III activity is increased in horses with exertional rhabdomyolysis.12
Severely affected horses are often hyponatremic (<130 mEq/L), hyperkalemic (>5.5 mEq/L), hypochloremic (<90 mEq/L), azotemic (increased serum urea nitrogen and creatinine concentrations) and acidotic or alkalotic. Hemoconcentration (hematocrit >50%, 0.5 L/L) and increased serum total protein concentration (>80 g/L) indicative of dehydration are common. Serum bicarbonate concentration can be falsely markedly elevated in animals with severe rhabdomyolysis because of cellular constituents released from damaged muscle that interfere with the analytical method when automated clinical chemistry analyzers are used.13 Measurement of urinary excretion or fractional excretion of electrolytes is not useful in detecting horses susceptible to recurrent exertional rhabdomyolysis.19
Myoglobinuria is detectable either grossly or on chemical analysis and should be differentiated from hemoglobinuria or hematuria. Measurement of urinary excretion of electrolytes, although popular in the past, is of no use in diagnosing, treating, or preventing exertional rhabdomyolysis.
Muscle biopsy during the acute or convalescent stages reveals myonecrosis of Type II (fast twitch, oxidative) fibers, mild myositis, and fibrosis.
Horses dying of exertional rhabdomyolysis have widespread degeneration of striated muscle; principally, the muscles of exertion, but often involving the diaphragm and heart. Affected muscles tend to be dark and swollen, but may have a pale, streaked appearance. The kidneys are swollen and have dark brown medullary streaks. Dark brown urine is present in the bladder. Histologic examination reveals widespread necrosis and hyaline degeneration of predominantly Type II (fast twitch, oxidative) fibers. In horses with recurrent disease there may be evidence of myofiber regeneration. Myoglobinuric nephrosis is present in severely affected horses.
Biochemical confirmation of muscle damage by demonstration of increased serum CK or AST activity, in conjunction with appropriate clinical signs, provides the diagnosis.
• Ear tick (Otobius megnini) induced muscle cramping20
• Polysaccharide storage myopathy of Quarter horses
• Casia occidentalis toxicosis
The treatment chosen depends on the severity of the disease. The general principles are rest, correction of dehydration and electrolyte abnormalities, prevention of complications including nephrosis and laminitis, and provision of analgesia.21
Mildly affected horses (heart rate <60 bpm, normal rectal temperature and respiratory rate, no dehydration) may be treated with rest and phenylbutazone (2.2 mg/kg, orally or IV every 12 hours for 2–4 days). Horses should be given mild exercise with incremental increases in workload as soon as they no longer have signs of muscle pain. Access to water should be unrestricted.
Severely affected horses (heart rate >60 bpm, rectal temperature >39°C (102°F), 8–10% dehydrated, reluctant or unable to walk) should not be exercised, including walking back to their stable, unless it is unavoidable. Isotonic, polyionic fluids, such as lactated Ringer’s solution, should be administered IV to severely affected horses to correct any dehydration and to insure a mild diuresis to prevent myoglobinuric nephropathy. Less severely affected horses can be treated by administration of fluids by nasogastric intubation (4–6 L every 2–3 hours). Affected horses should not be given diuretics.
Analgesia can be achieved by administration of phenylbutazone (2.2–4.4 mg/kg, IV or orally, every 12–24 hours), flunixin meglumine (1 mg/kg IV every 8 hours) or ketoprofen (2.2 mg/kg IV every 12 hours). Mild sedation (acepromazine or acetylpromazine 0.02–0.04 mg/kg IM, or xylazine, 0.1 mg/kg IM, both with butorphanol, 0.01–0.02 mg/kg) may decrease muscle pain and anxiety. Tranquillizers with vasodilatory activity, such as acetylpromazine, should only be given to horses that are well hydrated. Muscle relaxants, such as methocarbamol, are often used but have no demonstrated efficacy.
Recumbent horses should be deeply bedded and repositioned by rolling every 2–4 hours. Severely affected horses should not be forced to stand.
Prevention centers on insuring that horses are fed a balanced ration with adequate levels of vitamin E, selenium and electrolytes, and have a regular and consistent program of exercise.
Thorougbred race horses in training consume diets providing over 30 Mcal/day. The high energy intake is associated with increased risk of exertional rhabdomyolysis, especially if the diet provides a large (40%) of calories as readily digested carbohydrate (starch). Diets in which fat provides 20% of digestible energy calories and 7% as starch are associated with lower serum creatine kinase activities after exercise on a treadmill.14 These finding have been extrapolated to provide the recommendation that race horses in training receive no more than 20% of daily digestible energy from hydrolysable carbohydrate (starch) and at least 20% of DE from fat.22 Fat can be incorporated into the diet as rice bran, soy bean hulls, and vegetable (but not animal) fats and oils. High fat, high fiber commercial diets that are formulated for treatment of horses with polysaccharide storage myopathy or recurrent exertional myopathy are available.
Despite lack of clear evidence for a widespread role for vitamin E or selenium deficiency in exertional rhabdomyolysis, horses are often supplemented with 1 iu/kg of vitamin E and 2.5 μg/kg of selenium daily in the feed. Care should be taken not to induce selenium toxicosis. Sodium bicarbonate and other electrolytes are often added to the feed of affected horses, but their efficacy is not documented and is suspect.14
Phenytoin has proven useful in the treatment of recurrent rhabdomyolysis. It is administered at a dose rate of 6–8 mg/kg, orally, every 12 hours, and the dose adjusted depending on the degree of sedation produced (a reduced dose should be used if the horse becomes sedated) or lack of effect on serum CK or AST activity. Phenytoin can be administered to horses for months. Dantrolene (800 mg, approximately 2 mg/kg, orally 60 minutes before exercise) was demonstrated in a controlled, cross-over field trial of 77 horses, to be effective in reducing exercise-induced increases in CK and incidence of episodes of recurrent exertional rhabdomyolysis in Thoroughbred race horses.23 Similar results were obtained in 4 horses with recurrent exertional rhabdomyolysis administered 4 mg/kg orally 90 minutes before exercise on a treadmill.24
Dimethylglycine, dantrolene, altrenogest and progesterone are all used on occasion in horses with recurrent rhabdomyolysis, but again without demonstrated efficacy.
1 MacLeay JM, et al. Am J Vet Res. 1999;60:250.
2 Dranchak PK, et al. J Am Vet Med Assoc. 2005;227:762.
3 Lentz LR, et al. Am J Vet Res. 2002;63:1724.
4 Lentz LR, et al. Am J Vet Res. 1999;60:992.
5 Ward TL, et al. Am J Vet Res. 2000;61:242.
6 Collinder E, et al. Equine Vet J. 1997;29:117.
7 Cole FL, et al. Vet Rec. 2004;155:625.
8 MacLeay JM, et al. Am J Vet Res. 1999;60:1562.
9 Upjohn MM, et al. Vet Rec. 2005;156:763.
10 McGowan CM, et al. Vet Rec. 2002;151:623.
11 Toutain PL, et al. J Vet Pharmacol Therap. 1995;18:226.
12 Nishita T, et al. Am J Vet Res. 1995;56:162.
13 Collins ND, et al. Vet Clin Pathol. 1998;27:85.
14 McKenzie EC, et al. J Vet Int Med. 2003;17:693.
15 MacLeay JM, et al. Am J Vet Res. 2000;61:1390.
16 Bailey CJ, et al. Vet Rec. 1999;145:487.
17 Piercy RJ, Rivero JL. Equine Sports Medicine and Surgery. London: Elsevier, 2004;77.
18 Valberg S, et al. Equine Vet J. 1993;25:11.
19 McKenzie EC, et al. Am J Vet Res. 2002;63:1053.
20 Madigan JE, et al. J Am Vet Assoc. 1995;207:74.
21 Andrews FM. Vet Clin North Am: Equine Pract. 1994;10:567.
22 Geor RJ. Equine Sports Medicine and Surgery: Basic and clinical sciences of the Equine athlete. London: Elsevier, 2004;827.
Etiology Inherited defect caused by an autosomal recessive gene at a single locus with incomplete penetrance. Also known as the halothane sensitivity gene, or PSS mutation, which is a single point mutation of nucleotide 1843 in the skeletal muscle gene for the calcium-release channel of the sarcoplasmic reticulum.
Epidemiology Worldwide in major breeds of swine: Landrace, Yorkshire, Duroc, Pietrain, and Poland China. Market weight pigs, and adult sows and boars. Prevalence of defective gene varies between breeds and countries. Syndromes precipitated by stress of transportation, high environmental temperatures and humidity, exhaustive exercise, and by halothane anesthesia. Major economic importance because of deaths and poor quality pork.
• Porcine stress syndrome: death during transportation
• Malignant hyperthermia: induced by halothane anesthesia resulting in muscular rigidity and death
• Pale, soft, exudative pork: rapid rigor mortis after slaughter followed by excessive dripping of carcass and pale watery pork. Dark, firm, and dry pork is variation
• Back muscle necrosis: reluctance to move, acute swelling and pain over back and some may die; subacute form too.
Clinical pathology Halothane test. Blood creatine kinase test. Blood typing. DNA-based test for PSS mutation gene.
Lesions Pale skeletal muscles in PSS deaths. Pale muscles in back muscle necrosis.
Diagnostic confirmation Necropsy findings. Identification of homozygous animals with tests.
Control Genetic selection. Reduction of environmental and management stressors.
Three closely related stress syndromes occur in pigs. The porcine stress syndrome (PSS) is characterized by acute death induced by stressors such as transport, high ambient temperature, exercise and fighting, which results in progressive dyspnea, hyperthermia, disseminated vasoconstriction and the rapid onset of rigor mortis. Pale, soft and exudative pork (PSE) occurs post mortem in some pigs slaughtered by conventional methods. Malignant hyperthermia (MH) is a drug-induced stress syndrome characterized by muscle rigidity and hyperthermia occurring in susceptible pigs following the use of halothane or the muscle-relaxant suxamethonium. Back muscle necrosis of pigs is a special manifestation of the PSS.
Malignant hyperthermia also occurs in humans.1
PSS is caused by an inherited defect due to an autosomal recessive gene at a single locus with incomplete penetrance. It is also known as the halothane sensitivity gene, or PSS mutation, which is single point mutation of nucleotide 1843 in the skeletal muscle gene for the calcium-release channel of the sarcoplasmic reticulum. The PSS defect renders muscle hypersensitive to stimulation by various stressors. In stress-susceptible pigs there is a rapid onset of anaerobic glycolysis and loss of control of skeletal muscle metabolism in response to stress and anoxia.
The gene is commonly known as the halothane-sensitivity gene (HAL gene) because pigs with the homozygous genotype can be identified with the halothane test which results in malignant hyperthermia. The halothane gene is located within a group of blood type genes on the same chromosome allowing identification of affected pigs by blood typing. A single point mutation in the porcine gene for the skeletal muscle ryanodine receptor is associated with malignant hyperthermia in five major breeds of heavily muscled swine.2,3 Comparison of the sequences of the HAL genes of porcine stress syndrome and normal pigs revealed a single mutation at nucleotide 1843 in the cDNA derived from the HAL gene.2 The literature on the causative mutation for the porcine stress syndrome has been reviewed.4
This subject needs to be kept in perspective. It has recently been suggested that only 4% of inferior quality meat is due to genetics (halothane positive) with the remainder being due to pre-slaughter and post-slaughter treatment.5
PSS occurs worldwide, but there is considerable breed and area variation in its prevalence. In some European countries the prevalence is a major problem in pig production because of the inadvertent selection for this trait in genetic improvement programs. This underlies the problems of selection based purely on performance and production characteristics.
The prevalence of PSS in the swine population can be determined by the use of screening tests applied on the farm or when pigs enter swine performance test stations. The halothane test and the creatine kinase (CK) test are useful for this purpose. A DNA-based test with 99% accuracy is also available.6 Surveys in the UK found that the prevalence in the British Landrace varies from 0 to 23% of herds with an average of 11%. In European breeds, the prevalence varies from 0 to 88% with up to 100% in the Pietrain breed. None is present in the Large White breed although one isolated report describes malignant hyperthermia in a single Large White pig. The prevalence of halothane susceptibility is low in the Danish Landrace breed in Denmark.7 Based on the halothane test, 1.5% of young boars entering a Record of Performance Test Station in Canada were positive reactors. The reactors originated from 7.5% of 107 herds. The halothane succinylcholine test was a more sensitive test because 18% of the same pigs were identified as reactors.
Using a DNA-based test, in a survey of 10 245 breeding swine of various breeds from 129 farms in the US, Canada, and England, approximately 1 of 5 pigs was a heterozygous carrier of the PSS mutation, and 1% were homozygous.6 The prevalence of the PSS mutation was 97% for 58 Pietrain, 35% for 1962 Landrace, 15% for 718 Duroc, 19% for 720 Large White, 14% for 496 Hampshire, 19% for 1727 Yorkshire, and 16% for 3446 crossbred swine. The PSS gene frequencies for these breeds were 0.72, 0.19, 0.08, 0.10, 0.07, 0.10, and 0.09, respectively. The PSS mutation has also been identified in Poland China and Berkshire breeds. These gene frequencies were 30–75% lower in Canadian swine than in US swine, with the exception of Yorkshires, for which the gene frequency is threefold in Canadian swine.6
Susceptibility to the PSS is inherited and the biochemical events leading to PSE, transport death, or malignant hyperthermia are triggered by several external influences or stressors in the living animal. PSS probably occurs in all breeds of pigs, but the incidence is highest in pigs selected for heavy muscling, and stress-susceptible pigs are leaner and more meaty. These include the Pietrain and Poland China breeds and also some European strains of Landrace where a score for muscling as well as growth rate, feed conversion, and back fat has been included in the selection index. A recent study has shown that there are considerable breed differences in that halothane stress susceptible pigs and Hampshires suffer more severely from heat stress than Yorkshires, Danish Landrace, and Duroc boars.8
There is a correlation between halothane susceptibility and carcass traits. Halothane status is the most important factor influencing pork quality, although pre-slaughter handling and stunning method also influence the carcass quality.9,10
Halothane-positive animals usually score higher for visual conformation of the loin and ham than pigs which are halothane-negative. The progeny of reactor boars are also more susceptible than the progeny of non-reactors. Until recently it was thought that the major limitation of the halothane test was that it identified only those pigs which are stress-susceptible to the syndrome. It is now known that the halothane-sensitivity gene is expressed in heterozygous pigs where it is likely to cause poor carcass quality.
The gene for the porcine calcium channel has been sequenced and the site of the causative mutation located.2 The mutation was found in 5 major breeds of swine: Landrace, Yorkshire, Duroc, Pietrain, and Poland China. The prevalence of the gene in certain breeds in North America and England is given above.
Landrace pigs can be divided into those which are sensitive to halothane and develop pale, soft, exudative pork post mortem, those which are resistant to halothane but develop pale, soft, exudative pork, and those resistant to halothane and pale, soft, exudative pork (the normal pig). Muscle from pigs susceptible to malignant hyperthermia and pale, soft, exudative pork has significantly higher glucose-6-phosphate levels and lower phosphocreatine under thiopentone anesthesia than muscle from pigs susceptible to PSE and normal pigs. Altered muscle fiber type is not the primary basis of the disease complex.
The most important precipitating factors are transportation at high environmental temperatures and humidity, exhaustive exercise, and under experimental conditions, the more specific reaction towards the anesthetic halothane. Response of pigs to transport is dependent on genotype particularly at high temperatures such as 36°C.11 Experimentally, psychological mechanisms can precipitate the PSS. The effects of mixing, transportation, and duration of lairage can have profound effects on carcass characteristics of susceptible pigs. Death during transportation and PSE are associated with fear, defensive or aggressive reactions in unfamiliar social environments, or conflict with other strange pigs or man. Other activities which may trigger malignant hyperthermia include restraint, mating, farrowing, fighting, and vigorous exercising.
The economic losses associated with the PSS are due to mortality from transport death and inferior meat quality due to pale, soft, exudative pork. As a result of the excessive rates of production of lactic acid and heat, sarcoplasmic proteins denature, thereby causing a deterioration of the water-binding capacity of muscle. The increased osmotic activity due to end-products of hypermetabolism causes an influx of water from the extracellular space resulting in hemoconcentration and increased intramyofiber water content. The muscle becomes pale, soft, and exudative, sour-smelling and loose-textured. The shrinkage due to water loss during storage, transport and processing of the carcass is the major cause of wholesale losses at pork packing plants. PSE carcasses yield less bacon and the drip loss from fresh PSE meat is more than doubled compared to normal carcasses. Another cause of lost revenue with malignant hyperthermia susceptible swine is their decreased average daily weight gains, conception rates, litter sizes, and boar breeding performance.
The molecular basis for susceptibility to the PSS is a hypersensitive triggering mechanism of the calcium-release channel of skeletal muscle sarcoplasmic reticulum.6 The calcium channel, also known as the ryanodine receptor, plays a critical role in the initiation of muscle contraction. The PSS defect renders muscle hypersensitive to stimulation by various stressors. Stress-susceptible pigs cannot tolerate stress and lose control of skeletal muscle metabolism. The stress may be from external influences such as transportation, fear and excitement, or halothane anesthesia. There is excessive catecholamine release and the sudden onset of anaerobic glycolysis of skeletal muscle, excessive production of lactate and excessive heat production which, in conjunction with peripheral vasoconstriction, leads to hyperthermia. Following exertional or thermal stress, susceptible pigs undergo more extensive physiological change than do resistant pigs. Halothane sensitive pigs are more susceptible to becoming non-ambulatory and when subjected to multiple stressors and may be more prone to producing inferior pork products.10 The blood glucose concentrations are dependent on the malignant hyperthermia genotype; the homozygous positive animals having the highest levels and the homozygous negative animals having the lowest.12 The changes in carbohydrate metabolism at rest in malignant hyperthermia positive animals are caused by latent increases of intracellular Ca2+ concentrations. Under physical load conditions there is higher lipolysis which may be the result of an indirect activation of the lipolytic system via catecholamine induced cAMP turn-over.
Depending upon the nature, severity, and duration of the stress, the syndrome may manifest in different ways:
• The porcine stress syndrome causes rapid death following severe stress.
• The pale, soft, and exudative (PSE) pork and dark, firm, dry (DFD) pork are seen after slaughter which may have been preceded by mild stressors during lairage
Pale, soft, exudative pork is attributed to increased glycolysis after slaughter. In muscles which develop dark, firm, dry pork, the muscle glycogen is already depleted before slaughter.13 When PSE develops in a muscle, pH drops to values lower than 5.8 at 45 minutes after death. In normal muscles, the pH decreases from approximately 7 in living muscles to 5.3 to 5.8 at 24 hours after death. The lower pH in PSE muscles, combined with a high carcass temperature within the first hour after death, causes the proteins in the muscles to denature. This contributes to the pale color of PSE meat and to its reduced water-holding capacity. Development of muscles with PSE characteristics seems to be initiated by a combination of lower muscle pH already at exsanguination and a faster pH decrease.13
Malignant hyperthermia is the drug-induced, often fatal, stress syndrome occurring in susceptible pigs within 3 minutes following the inhalation of a mixture of halothane and oxygen.14 Susceptible pigs develop limb rigidity and a hyperthermia which are not easily reversed and may result in death. There is an increased rate of intracellular ATP hydrolysis leading to a progressive failure of ATP-dependent Ca2+ accumulation by sarcoplasmic reticulum and/or the mitochondria with a rise in myoplasmic concentration of Ca2+ and consequent contraction of muscle. The same molecular defect occurs in lymphocytes from affected susceptible pigs. There is no histomorphometric evidence of cardiac abnormalities in malignant hyperthermia susceptible pigs.15 The mitochondria from predominantly red muscle fibers have a greater calcium binding capacity than those from predominantly white muscle fiber areas. There is extreme rigidity of skeletal muscles, hyperthermia, tachycardia, cardiac arrhythmia, an increase in oxygen consumption, lactate formation and high-energy phosphate hydrolysis in muscle, respiratory and metabolic acidosis and a rise in the creatine kinase activity and concentration of potassium, lactate, glucose, free fatty acids and catecholamines in blood. There is a large release of glucose and potassium from the liver which contributes to the hyperglycemia and hyperkalemia. There is a marked α-adrenergic stimulation which is responsible for the heat production in malignant hyperthermia susceptible pigs. However, the β-adrenergic response in stress-sensitive and stress-resistant pigs is inconsistent.16 The lactic acidemia is severe due to the overproduction of lactate peripherally and failure of normal lactate uptake.
Malignant hyperthermia can also be induced using methoxyflurane, isoflurane and enflurane, and succinylcholine.
Exposing stress-susceptible pigs to halothane or exercise induces glycolysis but the mechanisms are different. There are no histochemical differences between muscles of susceptible and normal swine. There is some indication that halothane causes a transient but significant vasoconstrictive action which could be a contributing factor in initiating the severe reactions in malignant hyperthermia. Electron microscopy of platelets from stress-susceptible pigs reveals a defect characterized by dilatation of the open canalicular system.
Death during or following transport to market may be significant and is more prevalent when overcrowding occurs and during the hot summer period.17 If seen alive, affected pigs initially show a rapid tremor of the tail, general stiffness associated with increased muscular rigidity, and dyspnea to the extent of mouth-breathing. The body temperature is elevated, often beyond the limits of the clinical thermometer, and there are irregularly shaped areas of skin blanching and erythema. At this stage the affected pig is frequently attacked by other pigs within the group. The pig collapses and dies shortly afterwards and the total time course of the syndrome is generally of the order of 4–6 minutes.
Malignant hyperthermia is also a manifestation of the PSS. It may be induced in stress-susceptible pigs by anesthesia with potent volatile anesthetics such as halothane or by the administration of succinylcholine. It is characterized by the development during anesthesia of increased muscle metabolism with muscular rigidity, lactic acidosis, and a marked increase in basal metabolic rate, increased oxygen consumption, carbon dioxide production and severe hyperthermia and tachycardia, tachyarrhythmia and death. Once fully developed the syndrome is irreversible. The syndrome poses a hazard in swine anesthesia which can be averted by prior medication with dantrolene and has received considerable study as a model for an analogous syndrome in man. It has also been used as a method for determining stress susceptibility for genetic selection programs.
In stress-susceptible pigs, after slaughter, the inferior quality of the meat with its pale, soft, exudative characteristics is obvious. This is due to excessive postmortem glycolysis with lactic acid production and a rapid fall in muscle pH with depigmentation and reduced water binding as a consequence. In affected muscle, rigor mortis occurs rapidly after slaughter, but then decreases so that affected carcasses have been ‘set’ and postmortem drip is excessive. Affected pork has a pH of less than 6 and generally a temperature of 41°C (106°F) or greater 45 minutes after slaughter, compared to the normal pork with a pH above 6 and a temperature less than 40°C (104°F). This causes denaturation of muscle proteins leading to affected meat which has inferior taste, cooking and processing qualities, and does not accept curing as readily. The occurrence of this syndrome is considerably influenced by the stress of transport and handling prior to and during slaughter, and this aspect of the syndrome is of major economic importance.9,18,19 Rapid chilling helps prevent PSE but chill type has no effect.20
Dark, firm, dry pork has darker color and higher ultimate pH than normal meat. In muscles which develop DFD the muscle glycogen is already depleted before slaughter, which may be related to prolonged transport with fasting.
Acute necrosis of the longissimus dorsi occurs in German Landrace pigs and other breeds. The acute syndrome lasts approximately 2 weeks and is characterized by swelling and pain over the back muscles with arching or lateral flexion of the spine and reluctance to move. The swelling and pain then subside, but there is atrophy of the affected muscle and development of a prominent spinal ridge. Some regeneration may occur after several months. Acute cases may die. The syndrome occurs in young adults weighing from 75 to 100 kg. The mild form may be undetectable except for pigs lying down near the feed trough. In the severe form, affected pigs may assume the dog-sitting position with a hunched-up back.
Several testing methods are available for predicting susceptibility.
The halothane test is highly reliable for the identification of pigs which are homozygous for the single recessive gene responsible for susceptibility to the PSS. However, the test is not 100% accurate because of the incomplete penetrance of the halothane sensitivity trait (not all homozygous malignant hyperthermic susceptible pigs react by developing limb rigidity). Penetrance of the halothane sensitivity trait is estimated to vary from 50 to 100% depending on the breed, herd, and investigators. The test detects the worst clinical outcomes, and will not identify all the pigs which will develop PSE. There is now evidence that it will detect the heterozygote.21 Stress-susceptible pigs are sensitive to halothane at 8 weeks of age and if the anesthetic challenge is removed immediately after obvious signs of limb rigidity develop and before the development of fulminant hyperthermia, the mortality from the procedure is negligible. Pigs that remain unreactive for a challenge period of 5 minutes are considered normal.
A halothane-sensitive muscle defect can be present in certain individuals which do not develop rigid malignant hyperthermic episodes on brief exposure to halothane. A longer halothane exposure combined with succinylcholine is required if these false negatives are to be identified. The halothane test has good predictive value for the occurrence of PSE. However, there may be breed variations as mentioned above.
A decrease in the amplitude of the phosphocreatine (PCr) signal in the in vivo 31P nuclear magnetic resonance spectrum of skeletal pigs is an early and 100% predictive measurement for the detection of malignant hyperthermia in anesthetized piglets.22 Nuclear magnetic resonance techniques such as magnetic resonance imaging and magnetic resonance spectroscopy are sensitive diagnostic aids for detecting the onset of PSS in young animals and for following the metabolic changes in muscle tissue during the syndrome.7
Halothane concentration markedly affects the outcome of halothane testing, and either higher halothane concentrations or longer exposure might be required to identify positive reactors in a heterogeneous population. The ionophore A23187, a lipophilic carboxylic antibiotic which binds and transports divalent cations across both natural and artificial membrane bilayers, allows clear differentiation between the muscles of normal and pathological animals and may be a useful adjunct to the halothane test.
The blood creatine kinase (CK) levels are higher in stress-susceptible pigs. Pigs are subjected to a standard exertion test and blood samples taken 8–24 hours later and analyzed for CK. The original work indicated a good correlation between the CK levels and the halothane test. There is also an increase in CK levels in pigs as they are transported from the farm to the abattoir. However, not all pigs which develop PSE have increased serum levels of CK. Increased CK activity is highest in stress-susceptible pigs of a certain phenotype Phi-B, and their total plasma CK levels are higher than non-reactors.23 The initial test was modified so that blood could be collected as drops on a filter paper and sent to a laboratory for identification by a bioluminescent technique. A recent evaluation of a commercial CK screening test using the method of bioluminescence compared with the halothane challenge test on young boars entering a Record of Performance Test Station revealed that it was an inadequate indicator of susceptibility to the PSS or MH. In a different study the CK levels of piglets 8–10 weeks of age predicted halothane-induced stress syndrome with an accuracy of 87–91%.
Plasma pyruvate kinase activity has been compared with CK activity as indicators of the PSS. Both enzymes are increased significantly in homozygous halothane-reacting pigs compared to non-reacting pigs. Pyruvate kinase activity was less variable within groups than CK activity which may allow more effective discrimination between the two different genotypes. However, age-related effects and the failure to identify heterozygotes may restrict the use of plasma pyruvate activity as a diagnostic test.
Blood typing is also used as a method for the identification of susceptible pigs. On one of the chromosomes of the pig, a region with four known loci has been identified. These loci contain the genes responsible for variants of the enzymes 6-phosphogluconate dehydrogenase and phosphoferose isomerase (PHI). The H-blood group system is determined by one of the loci, and halothane sensitivity is also determined by genes at a locus in this region. This region is of special interest because a close connection has been found between this and important carcass traits such as the PSE condition. Thus, blood grouping may be used to detect halothane-sensitive pigs as well as heterozygote carriers.
A DNA-based blood test can now be used to detect the HAL gene status.2,3 It can be adapted for rapid batch analysis of many samples simultaneously, is less invasive, and can be applied to as little as 50 μL of blood. The test is more than 99% accurate, is cost-effective, and can be used to determine the prevalence of the PSS mutation in various breeds of swine in various countries.6 A recent study showed that 23% of pigs classified as Hal-1843 free based on a DNA test responded abnormally to halothane anesthesia.24
This is evaluated by a meat quality index which combines meat color, pH at 24 hours postmortem, and water-binding capacity. Susceptible lines can be identified by carcass inspection and the results applied to sibling or progeny selection. A recent approach is the measurement of mitochondrial calcium efflux. Mitochondria isolated from Mm longissimus dorsi muscle exhibit a rate of Ca2+ efflux twice that of normal pigs. Most of the tests readily predict the worst examples of the syndrome but are not sufficiently precise to be able to identify tendencies towards it, which restricts their value in breeding programs.
Erythrocyte osmotic fragility may be correlated with malignant hyperthermia and is being examined as a possible aid in the determination of susceptibility.21
Any reliable test which can identify stress-susceptible pigs without using halothane testing is attractive. Increased peroxidation of the erythrocytes may be an improved diagnostic test for PSS.25 Differences in the levels of cortisol, creatinine, aspartate aminotransferase, and lactate dehydrogenase are highly significant between halothane-sensitive and halothane-negative lines of pigs.26
An allele specific PCR (AS-PCR) technique has been developed.27 A PCR followed by reduction endonuclease assay has been developed and used28 on plucked hair as a source of genomic DNA. In a test with this method 9 of 12 Pietrains were tested homozygous or heterozygous. A one-step procedure has been developed called mutagenically separated PCR (MS-PCR).29
In the PSS, rigor mortis is present immediately following death, and carcass putrefaction occurs more rapidly than normal. The viscera are congested and there is usually an increased quantity of pericardial fluid as well as pulmonary congestion and edema. The muscles – especially the gluteus medius, biceps femoris, and longissimus dorsi – are pale, wet, and soft. In back muscle necrosis, these changes appear grossly to be confined to the epaxial musculature. Histologically, the lesions in skeletal muscle may be minimal, and are easily obscured by autolysis. In some instances only interstitial edema is visible while in animals which have survived repeated episodes there is obvious phagocytosis of degenerate myofibers, with ongoing regeneration and fibrosis. The most typical microscopic finding is hypercontraction of myofibers, characterized by division of the cell into irregularly-sized segments by transverse and sometimes branching bands. Degenerate sarcoplasm of a floccular or sometimes hyaline character may be present. Degenerative changes may also be detected in myocardial cells.
• Genetic analysis – 50 g frozen muscle (DNA ANALYSIS) and hair for PCR tests.
• Histology – formalin-fixed skeletal muscle (several sections, including longissimus dorsi), heart (LM).
• Biochemistry – it has been reported that pigs with PSS develop metabolic acidosis in association with respiratory acidosis30 which is manifested as lower values of acid–base excess and HCO3 – with higher H+ concentrations and pCO2 than resistant pigs.
The acute nature of the PSS and its relation to stress serve to differentiate it from most other syndromes causing sudden death in market and adult sized pigs. The sudden death syndrome must be differentiated from:
• Acute septicemias due to salmonellosis, erysipelas, pasteurellosis, and anthrax
• Other causes of sudden death including intestinal volvulus, heat exhaustion, suffocation during transportation
• Hypocalcemic tetany resulting from severe vitamin D deficiency can produce a similar clinical syndrome
• Porcine viral encephalomyelitis may also result in a similar clinical syndrome in postweaned pigs. Pathological and biochemical examinations differentiate these from the PSS.
The acute syndromes are usually not treated. Several drugs are available for the protection of pigs against drug-induced malignant hyperthermia. A combination of acepromazine and droperidol will delay the onset or prevent the occurrence of halothane-induced malignant hyperthermia. Dantrolene is also effective for treatment and prevention.9 The therapeutic dose is 7.5 mg/kg BW. Carazolol is effective for the prevention of transport death when given 3–8 hours before transportation and improves meat quality compared to untreated susceptible animals. Acute back necrosis has been treated successfully with isopyrin and phenylbutazone. Experimentally, the supplementation of the diets of stress-susceptible pigs with vitamin E and C will provide some protective effect on cell membrane integrity.
The control of this syndrome depends on genetic selection and possible eradication of the PSS mutation and reduction of the severity of stress imposed on pigs.
The best strategy for control of this complex is not clear.6 Several factors must be considered. Swine homozygous for the PSS mutation are at very high risk for developing PSS and severe PSE to make them useful for market pigs. They are used primarily as a source of the PSS mutation for breeding programs and research purposes. Using swine which are heterozygous for the PSS mutation as market pigs may be advantageous. They benefit from the positive effects of the mutation, have minimal risk of developing PSS, and may have acceptable prevalence and severity of PSE, if during marketing and slaughter the environmental and management risk factors which precipitate PSE are minimized. The mutation is not a prerequisite for leanness and muscularity and it is possible for breeders to eradicate the gene from their breeding stock. The negative effects of the halothane gene on fresh pork quality are well known.31 However, such a policy may result in the loss of an easily accessible and cost-effective selection criterion for favorable carcass characteristics. The PSS mutation has been used successfully in most swine breeds for increasing leanness and muscling. With the development of the DNA-based test for the PSS mutation, the mutation can be selected for with high precision and accuracy, and its expression finely controlled in a breeding program.
The various testing methods described under clinical pathology are used to identify pigs with the halothane gene. The tests can be applied to breeding stock entering swine performance test stations or on a herd basis. A reliable diagnostic test such as a DNA-based blood test to identify it will provide the basis for elimination of the gene or its controlled inclusion in swine breeding programs.2
Control through reduction of stress is not easily applied because frequently the syndrome is induced by routine minor procedures within the piggery. The incidence of transport deaths or the necessity for immediate slaughter salvage of severely stressed pigs on arrival at the abattoir and the occurrence of pale, soft, exudative meat characteristics are a significant economic problem in some countries. The necessity to climb an upper deck in the transport poses a significant stress, and the use of single-deck transports or mechanical lifts for multiple-deck transports, and the shipment of pigs in containers has resulted in a decreased incidence. The provision of spacious, well-ventilated transport vehicles and spray-cooling of pigs on arrival at the holding pens is also beneficial. Pigs should not be slaughtered directly after arrival at the abattoir but should be rested for at least 1–2 hours if they have been stressed only by transportation. In cases of severe physical exertion even more time should be allowed for recovery. Where possible transport distance should be kept to a minimum and transport should be avoided on excessively hot days.
O’Brien PJ. The causative mutation for porcine stress syndrome. Comp Cont Educ Pract Vet. 1995;17:257-269.
Shen H, Lahucky R, Kovac L, O’Brien PJ. Comparison of HAL gene status with 31P NMR-determined muscle metabolites and with Ca sequestration activity of anoxia-challenged muscle from pigs homozygous and heterozygous for porcine stress syndrome. Pig News Info. 1992;13:105N-109N.
1 Louis CF, et al. Pig News Info. 1990;11:341.
2 Fujii J, et al. Science. 1991;253:448.
3 Shen H, et al. Pig News Info. 1992;13:105N.
4 O’Brien PJ. Comp Cont Educ Pract Vet. 1995;17:257.
5 Cassens RG, et al. Fd Chem. 2000;69:357.
6 O’Brien PJ, et al. J Am Vet Med Assoc. 1993;203:842.
7 Janzen EG, et al. Can J Anim Sci. 1994;74:37.
8 Tauson AH, et al. Anim Sci. 1998;66:431.
9 Channon HA, et al. Meat Sci. 2000;56:291.
10 Allison CP. Proc 18th Int Pig Vet Soc Cong 2004; 799.
11 Yoshioka GO, et al. Jap J Swine Sci. 2001;38:4.
12 Otten W, Eichner HM. Anim Sci. 1996;62:581.
13 Enfalt AC, et al. Meat Sci. 1993;34:131.
14 Bjurstrom S, et al. J Vet Med A. 1995;42:659.
15 O’Brien PJ, et al. Can J Vet Res. 1987;51:50.
16 Jones CA, et al. J Vet Pharmacol Ther. 1989;12:14.
17 Carrott RF, et al. Res Vet Sci. 1998;64:51.
18 D’Souza DN, et al. Aust J Agric Res. 1998;49:1021.
19 Van der Wal PG, et al. Meat Sci. 1999;53:101.
20 O’Neill DJ, et al. Pig J. 2003;51:74.
21 Gallant EM, et al. Am J Physiol. 1989;257:C781.
22 Decanniere C, et al. J Appl Physiol. 1993;75:955.
23 Doize F, et al. Can Vet J. 1992;33:263.
24 Rempel WE, et al. J Anim Sci. 1993;71:1395.
25 Duthie GG, et al. Am J Vet Res. 1989;50:84.
26 Schafer AL, et al. Can J Anim Sci. 1990;70:845.
27 Lee SH, et al. Anim Gen. 2002;33:237.
28 Bastos RG, et al. Gen Molec Biol. 2000;23:815.
29 Lockley AK, et al. Meat Sci. 1996;43:93.
Inherited defects of the skin
This is an inherited skin defect of cattle in which animals born with a normal hair coat lose hair from areas distributed symmetrically over the body. It has been observed in Holstein cattle as a rare disease but its appearance among valuable purebred cattle has economic importance. It appears to be inherited as a single autosomal recessive character. Loss of hair commences at 6 weeks to 6 months of age. The alopecia is symmetrical and commences on the head, neck, back, and hindquarters, and progresses to the root of the tail, down the legs, and over the forelimbs. Affected skin areas become completely bald. Pigmented and unpigmented skin is equally affected; there is no irritation and the animals are normal in other respects. Failure of hair fibers to develop in apparently normal follicles can be detected by skin biopsy.
In this congenital disease there is partial or complete absence of the hair coat with or without other defects of development. The main importance of the disease is in cattle, in which there are six syndromes, but it is also inherited in pigs, in which it is associated with low birth weights, weakness, and high mortality, and in Poll Dorset sheep, in which the face, ears, and lower legs are bald, there are no eyelashes, and the patient lacrimates excessively. The skin is thick, wrinkled, greasy, scaly, and erythematous. Hair fibers are completely absent from the follicles, but wool fibers and follicles are normal.1
The condition is recorded in North America in Guernsey and Jersey cattle. Calves are viable provided they are sheltered. They grow normally but are unable to withstand exposure to cold weather or hot sun. In most instances hair is completely absent from most of the body at birth but eyelashes and tactile hair are present about the feet and head. Occasionally hair may be present in varying amounts at birth but is lost soon afterwards. There is no defect of horn or hoof growth. The skin is normal but has a shiny, tanned appearance and on section no hair follicles are present in the skin. The condition is inherited as a single, recessive character.
Congenital hypotrichosis has been reported in a Perheron draught horse.2 At birth there were circumscribed patchy areas alopecia which was progressive becoming almost complete by 1 year of age. Skin biopsy at 7 months of age revealed severe follicular hypoplasia and the animal was still alive at 6 years of age.
This is a complete hypotrichosis in which the thyroid is abnormally small and hypofunctional and the calves die shortly after birth.
Congenital X-linked hypotrichosis with missing teeth in cattle is characterized by abnormal morphogenesis to teeth, hair follicles, and eccrine sweat glands.3 Two different forms can be distinguished according to the severity of the tooth defects: (1) congenital hypotrichosis with complete or almost complete anodontia; (2) congenital hypotrichosis with completely missing incisors or defective incisors. Impaired body condition and growth of the affected animals result from missing teeth. In addition, animals with sparse hair are more susceptible to cold and more prone to skin lesions.
The phenotype and inheritance of hypotrichosis with nearly complete anodontia has been recorded in pedigreed German Holstein calves.3 The phenotype is inherited as a monogenic X-linked recessive trait. A reverse transcription-PCR assay was used to identify the causative large genomic deletion in the bovine EDI gene. The EDI gene for the hypotrichosis and anodontia phenotype appears to have pleotropic effects on hair follicles, eccrine nasolabial glands, apocrine sweat glands, individually expressed contours of the muzzle, and on development of incisor and premolar/molar teeth. A molecular genetic test for the pathological mutation allows the unequivocal classification of animals with congenital hypotrichosis and anodontia and identification of heterozygous carriers and their exclusion from further breeding.3
A sex-linked semidominant gene causes development of a streaked hairlessness in which irregular narrow streaks of hypotrichosis occur in female Holsteins.
Recorded in polled and horned Hereford cattle. At birth there is a fine coat of short, curly hair which later is added to by the appearance of some very coarse, wiry hair. The calves survive but do not grow well. The character is inherited as a simple recessive. The disease in Poll Herefords has the same short curly coat but there is also a deficiency of hair in the switch, and over the poll, brisket, neck, and legs in some cattle. Some have a much lighter hair coat color. Histologically there is a characteristic accumulation of large trichohyaline granules in the hair follicles.
The ‘rat tail’ occurred following the importation of continental European breeds of cattle into the United States when those breeds were crossed with Angus or Holsteins.4 The abnormality is characterized by short, curly, malformed, sometimes sparse hair and lack of normal tail switch development. Histologically, there are enlarged, irregularly distribute, and clumped melanin granules in the hair shafts, which are asymmetrical, short, curled, and small. The scale surface is rough and pitted, and scale fails to form in some areas. A study of the inheritance of the abnormality found that all rat-tail calves were sired by Simmental bulls and were from cows with various percentages of Angus breeding.4 The abnormality had no effect on birth weight, weaning weight, or gain from birth to weaning. However, rat-tail calves had significantly lower rates of gain during the winter months from weaning to yearling than non-rat-tail calves. The syndrome is controlled by interacting genes at 2 loci. Cattle which express the syndrome must have at least one dominant gene for black color and be heterozygous at the other locus I
Some ‘buckskin’-colored follicular dysplasia occurs in so-called ‘Portugese’ Holstein cattle, a grade variant of Red Holsteins with a tan color instead of the red. This defect consists of a coat-color-linked hair follicle dysplasia, in which the colored hairs are shorter and less lustrous than the white hair, making the coat much finer and smoother. Test matings seem to confirm an autosomal dominant inheritance.1
A black hair colored follicular dysplasia is also recorded in Holstein cattle.2 Patches of hair loss varying from hypotrichosis to complete alopecia occur in a random fashion but only on black areas. Follicular dysplasia is evident in biopsy samples. The abnormality persists for the life of the animal and is of cosmetic importance only. An inherited etiology is assumed.
A follicular dysplasia in a mature Brangus-cross cow and a mature Angus cow has been described.3 Adult onset alopecia occurred and skin biopsy revealed follicular distortion and atrophy, with melanin clumping in follicular epithelium, hair bulb matrix cells, hair shafts, and infundibular keratin.
This is recorded in Merino and Welsh mountain sheep and characterized by a coat of hairy medullated fibers in contrast with the non-medullated wool fibers of the normal sheep fleece.
The Arab fading syndrome commences in young horses in particular families of Arab horses as round, unpigmented patches of skin around the lips, eyes, perineum, preputial orifice. Some cases recover spontaneously but the blemish is usually permanent.
Albinism is a congenital lack of melanin pigment in the skin, hair, and other normally pigmented structures such as the uveal tract. Albinism is classified as generalized or localized and as complete or partial or incomplete. The affected skin in albinism is characterized microscopically as melanopenic rather than melanocytopenic, which distinguishes partial albinism from piebaldism. Most of the normal, inherited white markings which occur on horses are localized forms of piebaldism. Generalized and complete albino animals (oculocutaneous albinism) have white hair, white skin, pink irides and usually exhibit photophobia.2 Generalized albinism in the horse is inherited as autosomal dominant trait which is only viable in the heterozygous states. These horses have incomplete albinism as there is some coloration to the iris. Matings of heterozygous albino horses produce a nonviable embryo 25% of the time which is resorbed in gestation. This is one form of lethal white foal syndrome. A second form of lethal white foal syndrome is an autosomal recessive defect which occurs by mating of overo paint horses. Lethal white foals from such breedings are characterized by albinism and congenital defects of the intestinal tract.
This is a lethal defect of Holstein-Friesian calves inherited as an autosomal recessive character. The calves, most commonly heifers, are normal at birth but at 1–2 months of age begin to lose condition in spite of good appetites. The skin over most of the body is slightly thickened, scaly, and relatively hairless. There are also patches of scaly, thickened, and folded skin especially over the neck and shoulders, and hairless, scaly, and often raw areas in the axillae and flanks and over the knees, hocks, and elbow joints. The skin over the joints is immovable. There is usually alopecia about the base of the ears and eyes. The tips of the ears are curled backwards. The horns fail to develop and there is persistent slobbering, although there are no mouth lesions. The hooves are long, narrow, and pointed because of gross overgrowth of the walls; these and stiffness of joints cause a shuffling, restricted gait. Calves assume a recumbent posture for most of the time. Severe emaciation leads to destruction at about 6 months of age.
Histological changes in the skin include acanthosis, hyperkeratosis, and patchy neutrophil invasion. The similarity of this condition to inherited parakeratosis and to experimental zinc deficiency suggests an error in zinc metabolism, but treatment with zinc had no effect on the course of the disease.1
Absence of mucous membrane, or more commonly, absence of skin over an area of the body surface has been recorded at birth in pigs, calves, lambs,1 and foals. There is complete absence of all layers of the skin in patches of varying size and distribution. In cattle the defect is usually on the lower parts of the limbs and sometimes on the muzzle and extending onto the buccal mucosa. The disease is best known in Holstein-Friesians, but is also recorded in Japanese Black, Shorthorn, Sahiwal,2 and Angus cattle. In pigs the skinless areas are seen on the flanks, sides, back, and other parts of the body. The defect is usually incompatible with life and most affected animals die within a few days. Inheritance of the defect in cattle is conditioned by a single recessive gene. Tissue-cultured fibroblasts from affected animals produce subnormal amounts of collagen and lipids.3
Suspected of being inherited, this defect in Angus calves is characterized by defective collagen bridges in the basal and prickle layers of the epidermis so that skin, normal at birth, is subsequently shed at carpal and metacarpophalangeal joints and coronet, and there is separation of horn at the coronet.
This congenital disease of Suffolk and South Dorset Down sheep4 and Simmental5 and Brangus calves is characterized by the formation of epidermal bullae in the mouth and on exposed areas of skin, such as the extremities of the limbs, the muzzles and ears, leading to shedding of the covering surface and separation of the horn from the coronet. Lesions may be present at birth. Simmental calves grow poorly, have hypotrichosis, and suffer repeated breaks in the skin, apparently due to an abnormal susceptibility to trauma. Most calves die but some survive and the lesions subside. In Simmentals the disease is inherited as an autosomal dominant trait. The disease in Brangus calves is very similar to familial acantholysis in Angus cattle.
The severe form of Herlitz junctional epidermolysis bullosa, which occurs in humans has been recorded in foals of the French draft horse breeds.6 A mutation in the LAMC2 gene is responsible for the defect. Affected foals were born with skin blistering, skin and buccal ulceration followed by loss of hooves. In the affected skin there was disjunction of the epidermis from the underlying dermis at the dermal-epidermal junction. Genomic DNA testing is used to determine the presence of the mutation in carrier animals.
This defect is inherited in Belgian foals, Angus and Simmental calves, and Suffolk and South Dorset Down lambs.7,8 It is usually recorded under the heading of epidermolysis bullosa. There may be no shedding of skin but the initial bullous lesions at the coronet, considered to be initiated by abrasions, lead to sloughing of the hooves.
This is similar to both of the above diseases. It is recorded in Scottish Blackface and Welsh mountain9 sheep. The lesions are not present at birth but become apparent at 2–4 days of age when there is sloughing of skin of the limbs, the accessory digits, the ear pinna, and of the epidermal layers of the cornea and buccal mucosa, especially the dorsum of the tongue. There is also an absence of head horn and a separation of hoof horn from the coronet. Pieces of horn become completely detached exposing the red corium below, hence ‘red foot’. The cutaneous and mucosal lesions often commence as blood-filled or fluid-filled blisters. The corneal lesions are similarly the result of sloughing of epidermal layers. Although the cause is unknown there are indications that it is inherited.
1 Tontis A, Hofstetter H. Schweiz Arch Tierheilkd. 1991;133:287.
2 Fordyce G, et al. Aust J Agric Res. 1987;38:2.
3 Frey T, et al. J Invest Dermatol. 1989;93:83.
4 Jolly RD, et al. New Z Vet J. 2004;52:52.
5 Bassett H. Vet Rec. 1987;121:8.
6 Milkenkovic D, et al. Genet Sel Evol. 2003;35:249.
7 Frame SR, et al. J Am Vet Med Assoc. 1988;193:1420.
Inherited as a single autosomal, incomplete dominant character in Bavarian Highland cattle, this anomaly affects both ears, appears at birth, and varies from a minor trimming up to a complete deformity and reduction in size.1
An inherited photosensitization with hyperbilirubinemia has been observed in Southdown sheep in New Zealand and the United States, and in Corriedales in California.1 It is inherited as an autosomal recessive trait.
Liver insufficiency is present but the liver is histologically normal. Phylloerythrin and bilirubin excretion by the liver is impeded and the accumulation of phylloerythrin in the bloodstream causes the photosensitization. There is also a significant deficiency in renal function. Symptomatic treatment of photosensitization and confining the animals indoors may enable the lambs to fatten to market weight. The persistent hyperbilirubinemia is accompanied by an inability of the kidneys of these sheep to concentrate urine and the eventual death of the sheep from renal insufficiency.
Affected sheep live for several years if they are protected from sunlight and tend to die from renal failure associated with progressive fibrosis of the kidney.
A similar disease in Corriedale sheep in California is inherited as an autosomal recessive trait.1 The functional defect is not in the uptake of unconjugated bilirubin and phylloerythrin, but rather its excretion from liver into bile. It affects lambs as they begin to eat pasture. Lambs live until 6 months of age if provided with some shade. There is also marked melanin-like pigmentation of the liver.
These two diseases are examples of the involvement of external environmental disease factors with a genetic disease: a diet of green forage (chlorophyll) and sunlight, working in concert with the inborn error of metabolism to induce photosensitization.1
Congenital ichthyosis is a disease characterized by alopecia and the presence of plates of horny epidermis covering the entire skin surface. It has been recorded only in Holstein and Norwegian Red Poll and probably in Brown Swiss calves among the domestic animals, although it occurs also in humans.
The newborn calf appears to be either partly or completely hairless and the skin is covered with thick, horny scales separated by fissures which follow the wrinkle lines of the skin.2 These may penetrate deeply and become ulcerated. There are plenty of normal hair follicles and normal hairs but these are lost in the areas covered by the growth of scales. A skin biopsy section will show a thick, tightly adherent layer of keratinized cells. The disease is incurable and, although it may be compatible with life, most affected animals are disposed of for esthetic reasons. The defect has been shown to be hereditary and to result form the influence of a single recessive gene.
This disease appears to be conditioned by the inheritance of a recessive, semilethal factor. Affected pigs may show defects at birth but in most instances lesions appear after birth and up to 3 weeks of age. The lesions occur at the coronets and on the skin.3 Those on the coronets consist of erythema and edema with a thickened, brittle, uneven hoof wall. Lesions on the belly and inner surface of the thigh commence as areas of erythema and become wart-like and covered with gray-brown crusts.
Many affected pigs die but some appear to recover completely. Many of the deaths appear to be due to the giant-cell pneumonitis which is an essential part of the disease. The pathology of the disease indicates that it is the result of a genetic defect which selectively affects mesodermal tissue. It is known to have originated in the Danish Landrace breed.
This is an extraordinary fragility of skin and connective tissue in general, with or without edema. It is probably inherited as a recessive character. It occurs in cattle, horses, in Finnish and White Dorper1 sheep, and a mild form is seen in Merino sheep. The latter is inherited as a simple autosomal recessive. The skin is hyperelastic, as are the articular ligaments; marked cutaneous fragility, delayed healing of skin wounds, and the development of papyraceous scars are also characteristic. Pieces of skin may be ripped off when affected sheep are being handled. In horses the skin in some parts of the body is thinner than elsewhere, e.g. the skin of the ventral abdomen and the collagen bundles in the area are more loosely packed and are curved rather than straight. The proportion of acid-soluble collagen is also much higher in this abnormal skin. The disease involves a molecular defect of a collagen-binding protein,2 and is related to a recognized problem in dogs and cats identified as ‘dominant collagen packing defect’.3
Hereditary equine regional dermal asthenia has been recorded in related Quarter horses in Brazil similar to that reported in the United States.4 Reported cases of horses with hyperextensible skin have involved Quarter Horses.5 Clinically there were bilateral asymmetrical lesions of the trunk and lumbar regions, where the skin was hyperextensible. Handling of the skin elicited a painful response and superficial trauma led to skin wounds. The skin was thinner than normal in affected areas, with thickened borders and harder fibrotic masses. Histologically, the collagen fibrils were thinner and smaller, which created a loose arrangement of collagen fibers within the deep dermis. The deep dermis contains a distinctive horizontal linear zone in which separation of collagen bundles results in formation of large empty cleft-like spaces between the upper and lower regions of the deep dermis: ‘zonal dermal separation’.5 Pedigree analysis indicates an autosomal recessive type of inheritance.
The Ehlers–Danlos syndrome, recorded in Charolais and Simmental cattle, and Rippolesa sheep,6 is also characterized by extreme fragility of skin and laxness of joints in the newborn. There is a defect in collagen synthesis, and histopathological findings include fragmentation and disorganization of collagen fibers.
The syndrome has also been recorded in lambs.7 The skin was loose and present in excessive amounts, with folds over the carpal joints and lower regions of the legs. In some lambs, there may be separation of epidermis from dermis with blood-filled cavitations and intact skin which can be easily torn.
Inherited cutaneous malignant melanoma are found in National Institute for Health (NIH miniature) and Sinclair miniature swine. Its expression is associated with two genetic loci, one of them associated with the swine major histocompatibility complex.1 Familial melanoma have also been recorded in members of successive litters from an individual Duroc x Slovak White sow.2
An inherited, congenital corneal opacity occurs in Holstein cattle. The cornea is a cloudy blue color at birth and both eyes are equally affected. Although the sight of affected animals is restricted they are not completely blind, and there are no other abnormalities of the orbit or the eyelids. Histologically there is edema and disruption of the corneal lamellae.
With lens dystrophy Brown Swiss cattle are affected by an inherited congenital blindness with a cloudy shrunken lens as the cause. Japanese Black cattle also suffer from an inherited blindness caused by defects in the pupil, retina, and optic disk.
Bilateral cataract has been observed to be an inherited defect in Romney sheep. It is inherited as an autosomal dominant and can be eradicated easily by culling.
Complete absence of the iris (aniridia) in both eyes is also recorded as an inherited defect in Belgian horses. Affected foals develop secondary cataract at about 2 months of age. Total absence of the retina in foals has also been recorded as being inherited in a recessive manner.
Microphthalmia is reported to be an inherited defect in Texel sheep, but the incidence is low. It is a well-recognized genetic defect of Texel sheep in Europe.1,2 Following importation and ‘breeding up’ of the breed in New Zealand in the 1990s, animals were released from quarantine for further expansion of the breed. The abnormality has occurred in a number of flocks in New Zealand and an experimental breeding flock is maintained to study the molecular genetics.3 It is inherited as an autosomal recessive trait. An outbreak in Texel sheep in New Zealand has been recorded.1 The optic globes are approximately one half normal size and the optic nerves at the chiasma are approximately one half normal size. No other lesions are present in any organs. The retina is composed of an irregular mass attached to and continuous with the ciliary apparatus at one pole, and connected to the optic nerve posteriorly by a short stalk.1 The morphology and morphogenesis of the defect has been followed in embryos at different ages from ewes known to be carriers of the microphthalmia factor.2 The primary event was abnormal development of the lens vesicle, with disintegration of the lens and subsequent overgrowth of mesenchymal tissue. The mesenchymal tissue later differentiated in various directions, whereas the epithelial structures found in the microphthalmic eyes at days 56 and 132 of gestation and in newborn lambs appeared to be remnants of the epithelial lens vesicle.
Typical colobomata, ophthalmoscopically visible defects of one or more structures of the eye, caused by an absence of tissue, have assumed a more prominent position than previously because of their high level of occurrence in Charolais cattle. The lesions are present at birth and do not progress beyond that stage. They affect vision very little, if at all. However, because they are defects they should be named in certificates of health but they are not usually considered as being a reason for disqualification from breeding programs. In Charolais cattle the inheritance of the defect is via an autosomal dominant gene with complete penetrance in males and partial (52%) penetrance in females. The prevalence may be as high as 6% and in most cases both eyes are affected. The defect is due to incomplete closure of one of the ocular structures at or near the line of the embryonic choroidal fissure. Failure of the fissue to close represents the beginnings of the coloboma. The retina, choroid, and sclera are usually all involved.
Entropion is inherited in a number of sheep breeds including Oxfords, Hampshires, and Suffolks. Affected lambs are not observed until about 3 weeks of age when attention is drawn to the eyelids of the apparent conjunctivitis. A temporary blindness results but even without treatment there is a marked improvement in the eyelids and the lambs do not appear to suffer any permanent harm.
Ocular dermoids are recorded as genetically transmitted in Hereford cattle. They occur as multiple small masses of dystrophic skin complete with hair on the conjunctiva of both eyes of affected cattle. They can be anywhere on the cornea, on the third eyelid, or the eyelid and may completely replace the cornea; there may be a resulting marked dysplasia of the internal ocular structures.
Although the vision appears unaffected a large number of congenital defects of the eye have been observed in cattle, including Herefords, affected by partial albinism. The defects include iridal heterochromia, tapetum fibrosum, and colobomas. Congenital blindness is also seen in cattle with white coat color, especially Shorthorns. The lesions are multiple and include retinal detachment, cataract, microphthalmia, persistent pupillary membrane, and vitreous hemorrhage. Internal hydrocephalus is present in some, and hypoplasia of optic nerves also occurs.
A combination of iridal hypoplasia, limbic dermoids and cataracts was recorded in the eyes of progeny of a Quarter Horse stallion, presumably as a result of a mutation in the stallion and transmission to the foals via an autosomal, dominant gene.4 The inheritance is a simple autosomal recessive.
Iridiremia (total or partial absence of iris), microphakia (smallness of the lens), ectopia lentis and cataract have been reported to occur together in Jersey calves. The mode of inheritance of the characters is as a simple recessive. The calves are almost completely blind but are normal in other respects and can be reared satisfactorily if they are hand-fed. Although the condition has been recorded only in Jerseys, similar defects, possibly inherited, have also been seen in Holsteins and Shorthorns.
Inherited night blindness occurs in Appaloosa horses which have otherwise normal sight. No defect has been described in the eyes.
Prolonged gestation occurs in cattle and sheep in several forms and is usually, although not always, inherited. The two recorded forms of the disease are prolonged gestation with fetal giantism and prolonged gestation with deformed or normal or small size fetuses.
The inherited disease is recorded in Holstein, Ayrshire, and Swedish cattle with prolongation of pregnancy from 3 weeks to 5 months. The cows may show marked abdominal distension but in most cases the abdomens are smaller than one would expect. Parturition, when it commences, is without preparation. Udder enlargement, relaxation of the pelvic ligaments, and loosening and swelling of the vulva do not occur and there is also poor relaxation of the cervix and a deficiency of cervical mucus.1 Dystocia is usual and cesarean section is advisable in Holstein cattle but the Ayrshire calves have all been reported as having been born without assistance. The calves are very large (48–80 kg body weight) and show other evidence of post-term growth, with a luxuriant hair coat and large, well-erupted teeth which are loose in their alveoli, but the birth weight is not directly related to the length of the gestation period.
The calves exhibit a labored respiration with diaphragmatic movements more evident than movements of the chest wall. They invariably die within a few hours in a hypoglycemic coma. At necropsy there is adenohypophyseal hypoplasia and hypoplasia of the adrenal cortex and the thyroid gland. The progesterone level in the peripheral blood of cows bearing affected calves does not fall before term as it does in normal cows.
This form of the disease has been observed in Guernsey, Jersey, and Ayrshire cattle. It differs from the previous form in that the fetuses are dead on delivery, show gross deformity of the head, and are smaller than the normal calves of these breeds born at term. In Guernseys the defect has been shown to be inherited as a single recessive character and it is probable that the same is true in Jerseys. The gestation period varies widely with a mean of 401 days.
Clinical examination of the dams carrying defective calves suggests that no development of the calf or placenta occurs after the seventh month of pregnancy. Death of the fetus is followed in 1–2 weeks by parturition unaccompanied by relaxation of the pelvic ligaments or vulva or by external signs of labor. The calf can usually be removed by forced traction because of its small size. Mammary gland enlargement does not occur until after parturition.
The calves are small and suffer varying degrees of hypotrichosis. There is hydrocephalus and in some cases distension of the gut and abdomen due to atresia of the jejunum. The bones are immature and the limbs are short. Abnormalities of the face include cyclopian eyes, microphthalmia, absence of the maxilla, and the presence of only one nostril. At necropsy there is partial or complete aplasia of the adenohypophysis. The neural stalk is present and extends to below the diaphragm sellae. Brain abnormalities vary from fusion of the cerebral hemispheres to moderate hydrocephalus. The other endocrine glands are also small and hypoplastic.
The disease has been produced experimentally in ewes by severe ablation of the pituitary gland, or destruction of the hypothalamus, or section of the pituitary stalk in the fetus and by adrenalectomy of the lamb or kid. Infusion of ACTH into ewes with prolonged gestation due to pituitary damage produces parturition but not if the ewes have been adrenalectomized beforehand.
Etiology Inherited immunodeficiency in foals of Arabian parentage caused by a mutation in the gene coding for DNA-protein kinase catalytic subunit.
Epidemiology Familial pattern of occurrence with autosommal recessive inheritance. Approximately 8% of Arabian horses are heterozygous for the mutation (carriers). Random mating results in approximately 1 in 600 foals being affected, but not all matings are random and the incidence of the disease is less than this number.
Clinical findings Foals normal at birth but succumb to systemic infection soon after birth and die before 3 months of age.
Death from acute septicemia, or recurrent or chronic continuous infection, usually of respiratory tract. Poor response to normally effective antibiotic therapy.
Clinical pathology Lymphopenia, hypogammaglobulinemia. PCR test detects animals heterozygous (carriers, parents of affected foals) or homozygous (affected foals) for the mutated gene.
Necropsy findings Thymic, lymph node, and splenic hypoplasia and a marked reduction in the numbers of splenic and lymph node lymphocytes.
Diagnostic confirmation. PCR detection of mutated gene (homozygouse in affected foals). Lymphopenia and agammaglobulinemia in a foal of Arabian breeding.
Control Ideally, elimination of the mutated gene by not breeding carrier animals. The disease can be prevented by not breeding a carrier animal to another carrier.
The fundamental defect is a 5 base-pair deletion in the specific gene that codes for DNA-dependent protein kinase.1-3 The gene is located on chromosome ECA9.4 This mutation causes a lack of activity of the catalytic subunit of DNA-dependent protein kinase.1,2,3 The deficiency of protein kinase activity, which is absolute in affected foals, results in the inability to join DNA strands that have been broken as part of the normal process of creation of V (variable) regions of T cell and B cell antigen receptors on lymphocytes. Without these receptors the lymphocytes are unable to respond to antigens and thus the foal is not capable of mounting adaptive, either cellular or humoral (antibody), immune responses.1
The immunodeficiency is inherited as an autosomal recessive defect. The disease occurs in purebred and part-Arabian horses. It has also occurred in an Appaloosa foal that had an Arab stallion in the fifth past generation of its mother’s pedigree. In one survey of Arabian foals in the United States, the prevalence rate of affected foals was 2.3% of 257 foals of Arabian breeding, and 25.7% of the parents of affected foals were estimated to be carriers of the genetic defect.5 However, this likely represents an overestimation of the incidence of the disease and prevalence of the mutation in the population of Arabian horses because of selective testing.6 The frequency of carriers of the mutation for severe combined immunodeficiency is approximately 8%, with an estimated 0.2% (1 in 600) of foals of random matings between Arabian horses affected with the disease, based on a survey of 250 horses.6 Approximately 17% of Arabian horses are heterozygous for the mutation and 0.3% of foals are homozygous among > 6000 horses tested by a commercial laboratory.7
Affected foals usually appear normal at birth, but are highly susceptible to infections from 2 to 65 days after birth and usually die from one or more infections by 3 months of age. The sires and dams of affected foals are clinically normal and have normal lymphocyte counts and serum immunoglobulin concentrations.
Affected foals are born with a combined immunodeficiency associated with a deficiency in both B-lymphocytes (which produce immunoglobulins) and T-lymphocytes (which provide cellular immunity). There is a marked lymphopenia and failure of immunoglobulin (Ig) synthesis and absence of delayed hypersensitivity of skin responses. Foals that receive immunoglobulins from the dam’s colostrum derive passive immunity and can survive for as long as 4 months. Foals that do not receive colostrum die much earlier. The cause of death is infectious disease.
Affected foals are susceptible to infections of all kinds, but mostly of the respiratory tract. Adenoviral pneumonia is considered to be the most common secondary complication, probably because adenovirus infection is so widespread in the horse population. Affected foals may also die from hepatitis, enteritis, or infection of other organs without pulmonary involvement. While adenoviral pneumonia is the most common complication, infections with bacteria and Pneumocystis carinii also occur. Cryptosporidium sp. has also been recorded in a number of foals with diarrhea, which is also a common complication.
Affected foals usually become ill from 10 to 35 days of age. Commonly there is a history suggesting a mild disease of the respiratory tract, especially the appearance of a bilateral nasal discharge, which often becomes sufficiently thick to interfere with sucking. The foal is unthrifty, lethargic, and tires easily but still nurses and eats solid feed. A deep dry cough and a serous to mucopurulent ocular and nasal discharge are common when pneumonia is present. There is moderate fever (39.5°C, 103°F) and an increase in the heart and respiratory rates. The depth of respirations is increased and a double expiratory effort is common. On auscultation, loud bronchial tones and moist and dry crackles are common over the anterior ventral aspects of both lungs. A chronic diarrhea is present in some foals, and alopecia and dermatitis, commonly associated with an infection by Dermatophilus congolensis, also occur. An important clinical feature is that affected foals do not respond favorably to treatment with antimicrobial agents. The course of the illness will vary from a few days to a few weeks and probably depends on the degree of immunodeficiency and the nature of the infection. Most affected foals become progressively worse over a period of 2–4 weeks, and death by 3 months of age is the usual outcome.
Lymphopenia is a constant finding with counts often less than 1000/mL and there is a concurrent hypogammaglobulinemia in foals that have not received colostrum. There is no IgM in precolostral serum of the foal. Following ingestion of colostrum, all subclasses of immunoglobulin will be present but in affected foals the level of IgM will steadily decrease weekly until at about 36 days when IgM is detectable. The lack of IgM is because of lack of synthesis and the shorter half life of this isotype of immunoglobulin in foals – serum IgG concentrations decline more slowly. Until the development of the PCR test for detection of homozygous foals and confirmation of the disease, the measurement of serum Ig concentrations was considered essential for a definitive diagnosis. Additional tests include enumeration of B-lymphocyte and T-lymphocyte responses to phytolectin stimulation and other tests of lymphocytic immunological function, but these tests are no longer required for diagnostic confirmation of the disease.
The lymph nodes are small and splenic follicles are not visible. A viral interstitial pneumonia and a secondary bacterial bronchopneumonia are common. The thymus gland is usually hypoplastic. Histologically the lymph nodes and spleen are depleted of lymphocytes, and germinal centers are absent. In some foals there are foci of necrosis of the intestinal epithelium but with minimal infiltration of inflammatory cells. Inclusion bodies of adenovirus may be present in the cells of several different body systems. In Australian foals Rhodococcus equi can be commonly isolated from pulmonary abscesses. Additional histological findings include a severe adenoviral pancreatitis and adenitis of the salivary glands.
Diagnostic confirmation in an apparently chronic case of pneumonia in a young foal depends on the identification of the characteristic lymphopenia.
The differential diagnosis list includes:
• Septicemia and pneumonia of foals, caused by Rhodococcus equi
• Agammaglobulinemia due to failure of transfer of maternal immunoglobulins from colostrum. In many foal populations as many as 20% of foals are immunodeficient for this reason
• Other immunodeficiencies (Table 35.1). Foals with these deficits are very susceptible to a variety of infectious diseases and are usually chronically ill, most often with respiratory infections. However, because they have partial protection, they survive and their life span is much longer than that of foals with CID, usually over 1 year and often 18 months. Hematologically the foal is normal unless an infection is in process, but electrophoretic examination usually reveals a marked deficiency of betaglobulins. Further tests are needed to identify the exact deficiency. A radioimmunodiffusion assay is used to quantitate serum immunoglobulins – IgA and IgM levels are usually at negligible levels, but IgG levels are discernible, although diminished. An intradermal test by injection of phytohemagglutinin determines T-lymphocyte status – a normal response is migration of mononuclear cells
• An isoimmune neonatal leukopenia can cause immune deficiency in foals; antibodies to the sire’s lymphocytes are detectable in the mare’s serum
There is no satisfactory treatment for CID in foals. Hyperimmune serum, whole blood transfusions, and broad-spectrum antibiotics are all used without more than a temporary response. Affected foals may be kept alive by twice-weekly injections of hyperimmune serum and a constant antibiotic cover. Immunotherapy using a transplant of bone marrow and a fetal thymus transplant has been attempted without success. Corticosteroids are contraindicated.
Horses heterozygous for the mutation can be detected using a commercial PCR assay.6,7 These horses have normal serum immunoglobulin concentrations and lymphocyte counts. Detection of heterozygous animals, which is required by some national breed organizations, is useful for several reasons. Firstly, it should, ideally, permit elimination of the disease from the population by breeding of only homozygous normal animals. However, this approach has not met with success because of the financial and emotional value of some heterozygous animals. Secondly, identification of the status of an animal permits controlled breeding such that the risk of producing homozygous affected foals is eliminated. This is achieved by mating only pairs of homozygous normal animals, in which case none of the off-spring will carry the mutated gene, or by mating a heterozygous animal with a homozygous normal animal. In this instance 1 in 4 of the progeny will carry the mutated gene, but none of the progeny will be homozygous for the mutated gene and, therefore, afflicted with the disease. This second approach, if applied consistently, should almost eliminate the disease.
1 Leber R, et al. Vet. Immunol. Immunopathol. 1998;65:1.
2 Wiler R, et al. Proc. Nat. Acad. Sci. 1995;92:485.
3 Shin EK, et al. J. Immunol. 1997;158:3565.
4 Bailey E, et al. Animal Genetics. 1997;28:268.
5 Poppi MJ, McGuire TC. J Am Vet Med Assoc. 1977;170:31.
6 Bernoco D, Bailey E. Animal Genetics. 1998;29:41.
7 http://www.vetgen.com/scidstats.html. Accessed August 13th, 2006.