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The Veterinary Journal
The Veterinary Journal 179 (2009) 336–347 www.elsevier.com/locate/tvjl


Equine diseases caused by known genetic mutations
Carrie J. Finno a,*, Sharon J. Spier b, Stephanie J. Valberg c
a Veterinary Medical Teaching Hospital, University of California, Davis 95616, USA Department of Medicine and Epidemiology, University of California, Davis, CA 95616, USA c Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA b

Accepted 25 March 2008

Abstract The recent development of equine genome maps by the equine genome community and the complete sequencing of the horse genome performed at the Broad Institute have accelerated the pace of genetic discovery. This review focuses on genetic diseases in the horse for which a mutation is currently known, including hyperkalemic periodic paralysis, severe combined immunodeficiency, overo lethal white syndrome, junctional epidermolysis bullosa, glycogen branching enzyme deficiency, malignant hyperthermia, hereditary equine regional dermal asthenia, and polysaccharide storage myopathy. Emphasis is placed on the prevalence, clinical signs, etiology, diagnosis, treatment and prognosis for each disease. Published by Elsevier Ltd.
Keywords: Genetics; Mutations; Hereditary; Horse

Introduction Greater interest will arise in genetic causes of disease when a specific breed is affected, when several related offspring are affected, or when developmental, congenital, or lethal traits are involved. The identification of genetic diseases has been hampered in horses due to their long gestation, single births, dispersion of horses after weaning, and existence of many diseases with delayed onset of expression or variable penetrance. Furthermore, there were limited tools available to study genetic diseases in horses until 2006, with advances in this field primarily relying on the occurrence of homologies in other species, using the comparative gene approach. The recent development of equine genome maps by the equine genome community (Spencer and Davis, 2007) and the complete sequencing of the horse genome performed at the Broad Institute under the auspices of the National Human Genome Research Institute have accelerated the

pace of genetic discovery. In 2007, genome mapping was used to identify two new genetic mutations for hereditary equine regional dermal asthenia (HERDA) and polysaccharide storage myopathy (PSSM). In addition to simple Mendelian genetic traits, these new technologies will provide the means to identify quantitative trait loci for multi-factorial traits in the near future. This review focuses on the genetic diseases in the horse for which a mutation is currently known. Hyperkalemic periodic paralysis (HYPP) Hyperkalemic periodic paralysis (HYPP) is an autosomal dominant trait affecting Quarter Horses, American Paint Horses, Appaloosas and Quarter Horse crossbred animals worldwide. The genetic disease has been associated with a Quarter Horse sire named Impressive and it has been estimated that 4% of the Quarter Horse breed may be affected (Bowling et al., 1996). Horses affected by HYPP may have been preferentially selected as breeding stock due to their phenotypic expression of well-developed musculature and favorable results in shows as superior halter


Corresponding author. Tel.: +1 530 752 0290; fax: +1 530 752 9815. E-mail address: cjfinno@vmth.ucdavis.edu (C.J. Finno).

1090-0233/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.tvjl.2008.03.016

1990). molasses. respectively) (Fig. 1992).1% of potassium in the total daily intake on a dry weight basis. Feeds high in potassium include alfalfa hay. and endoscopic findings include pharyngeal collapse and edema. hyperkalemia (6–9 mEq/L). Exercise does not appear to induce clinical signs and serum creatine kinase (CK) shows no change or a very modest increase during episodic fasciculations and weakness. clinical episodes begin with a period of brief hypotonia (twitching or delayed relaxation of muscles).. can occur in either H/H or N/H animals and may require a tracheostomy..1 The test for HYPP clearly differentiates between H/H. 1996). as other diseases can produce similar signs (e. Several horses have died during acute episodes (Cox. Clinical signs Clinical signs among horses affected by HYPP range from asymptomatic to daily muscle fasciculations and weakness resulting in recumbency. Rudolph et al. dog-sitting. the resting membrane potential is closer to firing than in normal horses (Pickar et al. In 2004. 1994b). Other precipitating factors include fasting. staggering. electrolyte derangements) and veterinarians may not be present during acute episodes. In most cases. Episodes of HYPP are often triggered by diets containing >1. with these results recorded on the Registration Certificate for all foals that descended from Impressive and were born after January 1. clinical signs may progress to swaying. / The Veterinary Journal 179 (2009) 336–347 337 horses (Naylor. although the H/H will have more frequent episodes and tend to show more severe signs of upper airway obstruction during an episode. 1990. 1985). The HYPP mutation results in a failure of a subpopulation of sodium channels to inactivate when serum-potassium concentrations are increased. 1991)... In 1996. or collapse is strongly suggestive of HYPP. Naylor. Etiology HYPP is due to a missense mutation (C to G substitution) resulting in a phenylalanine/leucine substitution in the alpha-subunit of the voltage-dependent skeletal muscle sodium channel alpha-subunit (SCN4A) (Rudolph et al.edu. Episodes last for variable periods. trailer rides and stress (Spier. Finno et al. Naylor.C. hemoconcentration. Foals may present for dysphagia or respiratory distress. N/H or N/N horses (homozygous affected. 2008).vgl. By the time training is initiated. Electromyographic examination of asymptomatic HYPP horses reveals abnormal fibrillation potentials. with some horses showing prolapse of the third eyelid. Diagnosis Descendents of the stallion Impressive on the sire or dam’s side in a horse with episodic muscle tremors. complex repetitive discharges with occasional myotonic poten- tials and trains of doublets between episodes (Spier et al. an excessive inward flux of sodium and outward flux of potassium ensues. In more severe attacks. . Horses that tested heterozygous affected for HYPP are designated as N/H and normal unaffected horses as N/N. usually 15–60 min. the AQHA ruled that foals born in 2007 or later and that tested homozygous affected for HYPP (H/H) would not be eligible for registration. electrolyte supplements and kelp-based supplements (Reynolds et al. Serum-potassium concentration returns 1 See www. neck and shoulders. myotonia. the definitive test for identifying HYPP is the demonstration of the base-pair sequence substitution in SCN4A (Rudolph et al.g. 2006). due to paralysis of upper respiratory muscles. The SCN4A gene was mapped to chromosome 11 at 14247699–14275289 (University of California Santa Cruz.. yet remain relatively bright and alert. During mild attacks. heterozygous affected. Submission of mane or tail hair with roots should be made to a licensed laboratory such as the Veterinary Genetics Laboratory at the University of California at Davis.J. 1994a). 1). 1992).ucdavis. In horses with HYPP. and mild hyponatremia occur during clinical manifestations of the disease with normal acid-base balance (Spier et al. Affected homozygous horses also exhibit dysphonia (high-pitched whinny) even between episodes.. largyngopalatal dislocation and laryngeal paralysis (Carr et al. 1992. Sweating and muscle fasiculations are observed commonly in the flanks. Stimulation and attempts to move may exacerbate muscle tremors and some horses develop severe muscle cramping. 1998. Respiratory distress. horses appear normal. or recumbency within a few min.. Horses may be tachycardic and tachypneic during episodes. most N/H horses have shown intermittent clinical signs with no apparent abnormalities between episodes (Spier et al. exertional rhabdomyolysis. the American Quarter Horse Association (AQHA) officially recognized HYPP as a genetic defect or undesirable trait and mandatory testing for HYPP was instituted. anesthesia or heavy sedation. Foals homozygous for HYPP usually show clinical signs of disease in the first few days of life. neurologic disorders. After an episode of HYPP subsides. Episodes of weakness or paralysis appear similar between N/H and H/H horses. As a result. However.. In heterozygous or homozygous HYPP horses. 1998). horses remain standing. weakness. 1994b). or normal. resulting in persistent depolarization of muscle cells followed by temporary weakness. Clinical signs in H/H foals include respiratory stridor and periodic obstruction of the upper respiratory tract. 1990. Foals that are heterozygous N/H are less severely affected and typically do not demonstrate clinical signs of disease until they are weaned.. typically by 2–3 years of age. Sodium channels are normally briefly activated during the initial phase of the muscle-action potential.

Fig. although both induce an increase in renal potassium ATPase activity (Cox.6% and 1. Clinical signs Affected foals are clinically normal at birth as passive transfer confers protective immunity. Davis. Regular exercise and frequent turnout are beneficial.4 mL/kg of a 23% solution diluted in 1 L of 5% dextrose) will often provide immediate improvement. Many horses spontaneously recover from episodes of paralysis and may appear normal by the time a veterinarian arrives. University of California. 1994). Finno et al. Affected foals have been identified in Australia. administration of calcium gluconate (0. With severe dyspnea due to laryngeal or pharyngeal obstruction. 1998). The alleles are HYPP-N (normal) and HYPP-H (affected). 1994b). caused most frequently by adenovirus or Pneumocystis to normal after the cessation of clinical signs.2–0. Severe combined immunodeficiency (SCID) Severe combined immunodeficiency (SCID) is an autosomal recessive trait reported in Arabian horses. Horses with HYPP can graze pastures because the high water content of the pasture grass makes it unlikely .5% total potassium concentration and meals containing <33 g of potassium (Reynolds et al. Some affected horses may have normal serum-potassium concentrations during minor episodes of muscle fasciculations (Naylor. HYPP is manageable disorder. 1985). Feeding grain or corn syrup to stimulate insulin-mediated movement of potassium across cell membranes may be of benefit. based upon this frequency. breeding a heterozygous affected horse (N/H) to a normal horse (N/N) results in a 50% chance of producing a foal heterozygous for HYPP. although recurrent bouts may occur and severe episodes can be fatal. Treatment Light exercise when clinical signs are first observed can sometimes abort an episode in mild cases. Other treatment options include administration of epinephrine (3 mL of 1:1000/500 kg intramuscularly [IM]) and administration of acetazolamide (3 mg/kg every 8–12 h orally [(PO]). 1978). 1978. Canada. a tracheostomy may be necessary. Breed registries and other associations have restrictions on the use of these drugs during competitions. while breeding a homozygous affected horse (H/H) to a normal horse (N/N) results in a 100% chance of producing a heterozygous affected horse (N/H). Since HYPP is a dominant trait. 1. acetazolamide (2–3 mg/ kg every 8–12 h PO) or hydrochlorothiazide (0.1–1. 1973. regardless of whether or not owners have witnessed clinical signs in their horses (Zhou et al.4% and. Owners of affected horses should advise veterinarians of HYPP status before anesthesia or procedures requiring heavy sedation. In severe cases..18% of Arabian foals would be expected to be homozygous for the gene (Bernoco and Bailey. An increase in extracellular calcium concentration raises the muscle-membrane threshold potential.. Owners of affected horses should be strongly discouraged from breeding these animals. acetazolamide stabilises blood glucose and potassium by stimulating insulin secretion. To reduce serum potassium..5–1 mg/kg every 12 h PO) may be helpful. These agents exert their effects through different mechanisms. In addition. / The Veterinary Journal 179 (2009) 336–347 that horses will consume large amounts of potassium in a short time. The age of onset of infection depends on the adequacy of passive transfer and the environmental challenge. Each sample is amplified with two pair of primers for an internal control of the PCR test. Great Britain and the United States (McGuire and Poppie. Control Decreasing dietary potassium and increasing renal losses of potassium are the primary steps taken to prevent HYPP episodes. 1978. Clark et al. but foals are then more susceptible to infectious disease and normally succumb by 5 months of age. The frequency of SCID gene carriers among Arabian horses in the United States was estimated at 8. IV dextrose (6 mL/kg of a 5% solution) alone or combined with sodium bicarbonate (1–2 mEq/kg) can be used to enhance intracellular movement of potassium. but usually occurs by 6–10 weeks post-partum. 1998). Studdert. All affected horses share the same mutation. Horses descended from Impressive should be tested for HYPP during pre-purchase examination. For horses with recurrent episodes of muscle fasiculations even after dietary alterations are instituted.338 C. DNA test for HYPP from the Veterinary Genetics Laboratory. which attenuates membrane hyperexcitability.J. Prognosis In most cases. Ideally. 0. Whitwell. horses with recurrent episodes of HYPP should be fed a balanced diet containing between 0. Diseases of the respiratory tract are common.

1973. Prognosis for affected foals is invariably grave. and an unstable mutant protein in the gene encoding the DNA-protein kinase catalytic subunit (DNA-PKcs) (Shin et al.C. is an autosomal recessive trait affecting foals of American Paint Horse. 3).vetgen. or overo lethal white foal syndrome (OLWS). A frame overo Paint Horse. Control and prognosis Genetic testing of breeding Arabians is recommended. 1978). Additional lesions include hepatic necrosis with biliary hyperplasia. diversity (D) and joining (J). / The Veterinary Journal 179 (2009) 336–347 339 carinii (McGuire et al. 1998... combine to form coding sequences of immunoglobulin and T-cell antigen receptor variable regions. Definitive diagnosis is based upon identification of the DNA-PKcs gene deletion in hair or blood samples through vetGen (www. 1974. tail or a small black body spot.. Quarter Horse and. Yang et al. Breeding of carriers of OLWS may produce foals that are all white or nearly all white and die from colic shortly after birth due to functional intestinal obstruction. however. 1978).. pleuritis and pericarditis (Perryman et al. Meningitis caused by listeriosis has been documented in a SCID foal (Clark et al. 1990) and is the equine variant of Hirschsprung disease. with no evidence of immunoglobulin production at the time of death (Ardans et al. 1978). immunologic reconstitution was completed in one SCID foal that was transplanted with 1. peritonitis. . a disorder affecting humans (Metallinos et al. 1987).. 1973.. 1977). rarely. However. This foal was monitored for 650 days and immunologic reconstitution remained complete. Intermittent diarrhea may also be observed (Studdert. The disorder has also been referred to as aganglionic megacolon (McCabe et al. 2. Perryman et al. including the entire PI3 kinase domain. 1978. For research purposes.. This V(D)J recombination is necessary for differential expression of antigen receptors on B and T lymphocytes. Studdert.. distinct gene segments called variable (V).8 Â 108 viable bone marrow cells/kg bodyweight (BW) that had been obtained from a histocompatible full sibling donor (Perryman et al. focal myocardial necrosis. 1978). 1978). 1978. The gene is located on chromosome 9 (Bailey et al. Diagnosis Prior to the discovery of the genetic mutation. Foals with SCID have a 967 amino acid deletion in the enzyme DNA-dependent protein kinase. Finno et al. 1997a. 1997b). During early lymphoid differentiation.. diagnosis of SCID was based on absolute lymphopenia (<1000/lL). 1978). University of California Santa Cruz. Etiology The genetic defect responsible for SCID is a five-basepair deletion (frameshift mutation) at codon 9480 resulting in a frameshift mutation and a 967 amino acid deletion from the C terminus. Studdert. Treatment is not recommended and affected foals should be euthanased. ulcerative enteritis. 1998).. Treatment Supportive care may prolong the course of disease. the absence of immunoglobulin M (IgM) in the pre-suckle serum and complete absence of germinal centers in lymphoid tissue and thymic hypoplasia at post-mortem examination (McGuire and Poppie. and breeding-stock solid (Santschi et al. 1978)... minimally blend overo. that the Fig. Perryman et al. lymphoid hypoplasia on lymph node histopathology. White coat-colored patterns with a low incidence of OLWS heterozygotes (<21%) include tobiano (Fig... frequently accompanied by secondary bacterial infection (McGuire and Poppie. Ileocolonic aganglionosis (overo lethal white foal syndrome) Ileocolonic aganglionosis. highly white calico overo and frame blend overo (Santschi et al.. sabino. A very high incidence (>94%) of OLWS heterozygotes is found in frame overo (Fig.com). In most cases.J. This deletion in the catalytic subunit of the DNA-PK causes DNA-PK to be inactive (Shin et al. 2). It is important to note. Thoroughbred breeds. bone marrow transplantation and thymus transplantation have been unsuccessful. but affected foals eventually die by 5 months. Studdert. 2001)... 1997). 1995). which is required for V(D)J recombination and for repair in the double-stranded DNA breaks (Wiler et al. 2001). foals with SCID have been treated with twice weekly IV administration of plasma hyperimmunised with antiadenovirus antibody and these foals have lived up to 11 months of age (Perryman et al. 2008). Affected foals lack both B and T lymphocytes and therefore lack an endogenous humoral or cell-mediated response. Some affected foals may have flecks of black hair in the main.

intact bullae are rarely seen and blisters are commonly noted (Knottenbelt et al. Comtois.. 1990).. Foals that have all white coat color patterns do not inexorably have OLWS. Vlaams Paard. Dominant white color patterns. Vonderfecht et al. 1983... albinos and some foals heterozygous for OLWS may have all white coats without aganglionosis. 2004). especially for non-frame overos. 3. The genetic test is also useful to determine carrier status. 17% of Belgian horses were carriers of the mutation and in Europe. tobianos.. and out-cropped Quarter Horses (horses with white color markings). .2 Treatment and prognosis There is no treatment available and the prognosis is invariably grave. The intestinal abnormalities are due to the complete absence of intrinsic myenteric plexus in the terminal small intestine. 1989. Both endothelin B receptor and endothelin 3 are essential for normal development of the enteric ganglia and melanocytes within the neural crest (Baynash et al. reddened erosions and ulcerations develop in the skin and mouth over pressure points or after mild trauma (Shapiro and McEwen. rectum and vulva.vgl. Granulation tissue along 2 Fig. 2003).... and along the coronary bands. Affected foals are homozygous for the Lys gene (Lys 118/Lys 118) and carriers are heterozygous (Ile 118/ See www. Some foals may be deaf and have blue eyes in addition to the pigment defects and aganglionosis (Vonderfecht et al. 1998). The equine Ile to Lys EDNRB substitution is in transmembrane domain one of a seven transmembrane domain G-protein coupled receptor for the endothelins. Since the skin is so fragile. 8–27% of horses of the Breton. and Belgische Koudbloed Flander draft horse breeds were carriers (Baird et al. 1994). Junctional epidermolysis bullosa (JEB) Junctional epidermolysis bullosa is an autosomal recessive trait affecting Belgians. The draft horse JEB mutation was not identified in a screening of 107 American Saddlebreds.ucdavis.. 2003). other draft breeds and American Saddlebred horses (Frame et al. cecum and entire colon. although radiographs. 1995). contrast studies and an ultrasound examination may be indicated to diagnose complete bowel obstruction. Diagnosis A white foal with signs of colic that does not pass any meconium is almost pathognomonic for the disease. Hosoda et al. but irregular. Kohn et al.. 2008). 1983). Embryologically..edu. Lieto et al. Extensive erosions may be present at mucocutaneous junctions of the mouth. Finno et al. Clinical signs Foals are typically born alive. White Paint foals without evidence of colic may not be homozygous for the OLWS mutation and should be genetically tested. Testing is available through the Veterinary Genetics Laboratory at the University of California at Davis. / The Veterinary Journal 179 (2009) 336–347 Lys 118) (Santschi et al. with the ileum most severely affected (Hultgren. 1982.J. 1983). 1982). Etiology The genetic defect responsible for OLWS is a single base-pair change (missense mutation) resulting in a isoleucine/lysine substitution at codon 118 of the endothelin receptor B (EDNRB) gene located on chromosome 17 at 49432374–49454137 (University of California Santa Cruz.. both melanocytes and myenteric ganglia cells are of neural crest origin and their failure to migrate from the neural crest results in the absence of melanocytes in the skin and aganglionosis of the intestine (Hultgren.. McCabe et al. In North America. 1998). 1994. A tobiano Paint Horse. Clinical signs Overo lethal white foal syndrome is characterised by a white coat and intestinal tract abnormalities that result in colic and related signs within 12 h of birth (Vonderfecht et al.. 1988. 2002. Milenkovic et al. The disease has also been referred to as equine epitheliogenesis imperfecta or hereditary junctional mechanobullous disease. A mutation causing JEB has been identified in Belgian horses. The colic is not responsive to analgesics and progressive abdominal distension will be seen with no fecal material passed. many solid (non-white coat color pattern) horses with Paint horse bloodlines are heterozygous and therefore the genotype can not necessarily be inferred from coat color patterns (Metallinos et al.340 C.

Affected foals may have flexural limb deformities. 5 See www. All affected foals studied to date have died or been euthanased by 18 weeks of age due to the severity of muscle weakness (Valberg and Mickelson.. 2001) located on chromosome 8 (Milenkovic et al... In Saddlebreds the clinical presentation has been compared to epitheliogenesis imperfecta (Lieto et al.edu. scarring.. Valberg and Mickelson. Laminin 5 is widely distributed in the basement membrane of epithelial tissues. 2002). Diagnosis A high index of suspicion is raised by typical clinical signs combined with skin biopsy findings of separation of the epidermis from the dermis by subepidermal clefts that are relatively free of inflammatory cells and debris (Johnson et al. Definitive diagnosis in draft horses requires DNA testing for JEB. which creates a branched structure through alpha 1. Glycogen is a required energy source in the rapidly growing fetus and neonate and is synthesized by glycogen synthase. 2002). aspartate transaminase and gamma glutamyl transferase (Valberg et al. Definitive diagnosis requires identification of the mutation in GBE1 by the University of California Veterinary Genetics Laboratory4 or Vet Gen.ucdavis. Periodic acid Schiff’s (PAS) stains are required for a histopathological diagnosis as they clearly show PAS positive globular inclusions with decreased normal background staining for glycogen in cardiac and skeletal muscle (Valberg et al.ucdavis. The absence of laminin 5 results in a cleft between the basement membrane zone of the dermal-epidermal junction. 2003). Secondary bacterial infections. which creates straight chains of glucose with alpha 1. The mutation for JEB in American Saddlebreds has not been identified but is suspected to involve the LAM a3 gene (Lieto. The foal may have temporary incisor teeth visible at birth that are white with irregular serrated edges and pitted enamel (Baird et al..C. Valberg et al. 2002). have recently been reported (Wagner et al. Etiology The genetic defect responsible for JEB in the Belgian and European draft breeds is a cytosine insertion (1368insC) creating a premature stop codon in the Lamc2 gene.. 2001. Glycogen branching enzyme deficiency (GBED) Glycogen branching enzyme deficiency (GBED) is an autosomal recessive disease affecting Quarter Horse and Pain Horse breeds.. 2008). Wagner et al. 2001). 2006).6-linkages. 2006).. liver and the brain cannot store or mobilise glycogen to maintain normal glucose homeostasis. 1995).com.3% in the Paint and Quarter horse breeds. The GBE1 gene was mapped to equine chromosome 26 at 33459264–33657117 (University of California Santa Cruz. Purkinje cells or cardiac myocytes may contain basophilic globules and eosinophilic crystalline material in hematoxylin and eosin stains (Valberg et al. 2001) (Fig. cardiac and skeletal muscle. 1988).vgl. 2006). 2002). 2001. Skeletal muscle.3 Treatment and prognosis There is no treatment for affected foals and they will eventually succumb to secondary infections or complete sloughing of the hooves. Wagner et al. Diagnosis Common hematologic findings include a leucopenia and moderate elevations in serum creatine kinase.. 1988). which encodes the laminin c2 subunit chain (Spirito et al. 2004). 1999...4-glycosidic linkages and by glycogen branching enzyme. Mane or tail hairs with roots intact or fetal liver tissue can be sub4 See www...edu... 2001).. / The Veterinary Journal 179 (2009) 336–347 341 the coronary bands may result in separation of the coronary bands from the hoof wall and sloughing of the hooves (Kohn et al. The truncated laminin c2 subunit chains lacks the C-terminal domain so it cannot interact with the other two subunits thereby preventing the formation of laminin 5 (Spirito et al. If the foal survives to term. Etiology GBED is due to a C to A point mutation at base 102 that results in a stop codon in exon 1 of the GBE1 gene encoding glycogen branching enzyme (Ward et al.vgl. See www. cardiac arrest or respiratory failure (Valberg et al. 2006). Clinical signs Many affected foals may be aborted or stillborn (Render et al. 4).. which is evident on microscopic evaluation of skin biopsies from affected foals (Johnson et al. 1988). 1989).1% 3 and 8. respectively. Carrier frequency estimates of 7.. The Lamc2 gene is located on chromosome 5 at 108228152–108279653 (University of California Santa Cruz. impaired alimentation due to oral lesions and death usually follow (Johnson et al. Tissues from GBED foals have no measurable GBE-enzyme activity or immuno-detectable GBE and cannot form normally branched glycogen (Valberg et al.. 2008). it may appear weak and hypothermic at birth and may progress to sudden death following hypoglycemic seizures. As a result. Finno et al. .vetgen. Corneal ulcers and dystrophic teeth are also described (Shapiro and McEwen.5 which are both licensed by the University of Minnesota to perform the test. 2001.J. 2006)..

Hematologic changes measured 2 min after death included hemoconcentration.J. Note the little normal background staining for glycogen and accumulation of large globular as well as smaller crystalline inclusions of polysaccharide. is an autosomal recessive trait affecting Quarter Horses and horses with Quarter horse lineage. The horse died of cardiopulmonary arrest and profound rigor mortis was present almost immediately. 2007). Hennig and Court. 2005). 1. hyperglycemia and elevated creatinine. Horses affected with HERDA may present with seromas or hematomas. with previous estimates ranging from 1. on average. open wounds or sloughing skin (Fig. 2004. 2005). Hereditary equine regional dermal asthenia (hyperelastosis cutis) Hereditary equine regional dermal asthenia (HERDA). 2005. 2004...5% (Tryon et al. mitted to determine if horses are affected or carriers of GBED. Other means to address hyperthermia and acidosis include external application of alcohol. / The Veterinary Journal 179 (2009) 336–347 L and myogobin was 10Â higher than the reference range. Treatment and prognosis There is no treatment for GBED and the prognosis is grave. fiber necrosis. Serum CK activity was mildly elevated at 843 U/ See www. once a fulminant episode is underway it is difficult to prevent cardiac arrest. Males and females are affected equally (White et al. It is not associated with recurrent exertional rhabdomyolysis (Dranchak et al. 6 Fig. Clinical signs Clinical signs of HERDA do not typically appear until horses are. the body temperature was 40. White et al.5% (Tryon et al. hyperkalemia. Tryon et al. 2006). a PCR based genetic test is now available. hyperphosphatemia. increased variation in fiber sizes.342 C. Finno et al.5 °C (104. fans. 1988). while a PaCO2 of 274 mmHg and a blood pH of 6. 2004). Diagnosis Classic episodes of malignant hyperthermia are diagnosed based on clinical signs of lactic acidosis and hyperthermia >40 °C under halothane anesthesia or following succinylcholine injection.vgl.8% to 6. Clinical signs One horse developed hyperthermia during an experimental protocol in which anesthesia was induced by delivering halothane via a face-mask without premedication (Aleman et al. 4. There is no cost effective means to deliver dantrolene to horses IV once an episode has begun. Unfortunately. Treatment and control The most successful outcome for a horse with suspected malignant hyperthermia would be pretreatment with oral dantrolene (4 mg/kg) 30–60 min prior to anesthesia (Valverde et al.ucdavis.. Carrier frequency has been recently estimated at 3.. At the end of anesthesia. 2007). The prevalence of HERDA is higher in cutting horses and cow horses. 5). 1991).72 were recorded. the horse’s PaCO2 and rectal temperature rose precipitously despite an increase in minute ventilation. centrally located nuclei. 2005). .5 years of age and is frequently associated with initial saddling or trauma (Rashmir-Raven et al.. also known as hyperelastosis cutis. Malignant hyperthermia Etiology An autosomal dominant mutation has been identified in two Quarter Horses that developed marked hyperthermia and metabolic acidosis during inhalation anesthesia (Aleman et al. Semimembranosus muscle biopsy from a foal affected with GBED stained with Periodic Acid Schiff’s stain. The disease has been compared to Ehlers Danlos syndrome in humans (Hardy et al.6 It is not known whether this mutation is present in all horses that develop malignant hyperthermia or whether there may be other yet unidentified mutations that cause signs of hyperthermia and metabolic acidosis during anesthesia. chilled intravenous fluids with sodium bicarbonate and mechanical ventilation.. Both horses were homozygous for a mutation in exon 46 of the skeletal muscle ryanodine receptor gene (RYR1).. Muscle biopsy revealed mild myopathic changes including. 2007. glycogen depletion and ringbinden fibers..9 °F). 1990a.edu.. The prevalence of the RYR1 mutation in Quarter Horses is not known at this time. hypercalcemia. After approximately 60 min of anesthesia.. Based on the discovery of a genetic mutation in two Quarter Horses.. It is important to test aborted foals and stillborns for this disease or to test the dams for carrier status.

White et al.cornell. Fig. 2001. The acronyms EPSM and EPSSM have also been used for this condition. Etiology The genetic defect responsible for HERDA initially localized to equine chromosome 1 and subsequently a G to A substitution at codon 115 was identified in equine cyclophilin B (PPIB) (Tryon et al. Appaloosas.ucdavis. 2005.C. . loose easily tented skin that does not return to its original position (Fig. See www. 6... Warmbloods and draft breeds. A large hematoma developed at approximately 1. The true prevalence within the various Warmblood breeds has not been studied. Phenotype of HERDA-affected horses. Phenotype of HERDA-affected horses... McCue et al. Commonly observed histological changes on skin biopsies include thinning of the dermis. 2004. there is no effective therapy for HERDA.vgl. Finno et al.. A genetic test to screen for the mutation is available through the University of California at Davis7 and Cornell University. White et al. In Quarter Horse and Quarter Horse related breeds. 6). A distinctive horizontal linear zone in which separation of the collagen bundles resulted in the formation of a large empty cleft between the upper and lower regions of the deep dermis has been described in two HERDA cases (Brounts et al. 2006). Steinmann et al. PSSM appears to be a common disorder with almost 50% of muscle biopsies from Warmblood horses being diagnosed with PSSM (McCue et al. 2004). 2004).. American Paint Horses. Stannard. PSSM is rarely identified in Arabians and Thoroughbreds... 2006b). This gene likely plays a role in the protein folding of collagens (Bachinger.8 Treatment and prognosis Currently. 2004. Note the extensible skin in affected tissue that can be easily separated from underlying fascia. In Warmbloods. White et al. Affected areas are located primarily along the dorsum. 1978.vet. / The Veterinary Journal 179 (2009) 336–347 343 Fig. 1987..5 years of age along the dorsum of this affected horse. the exact means by which the recently discovered mutation causes disease is unknown. and white hairs at areas of hair regrowth (White et al.J. Polysaccharide storage myopathy (PSSM) Polysaccharide storage myopathy (PSSM) is a glycogen storage disorder affecting Quarter horses. 2004).. Hardy et al. 2000... Diagnosis Histological examination of skin biopsies was used as a means to diagnose HERDA prior to the development of the genetic test however samples from grossly normal skin are not helpful in distinguishing HERDA-affected horses from those not affected (Rashmir-Raven et al. Horses appear less likely to develop lesions during the winter and it has been suggested to keep horses indoors and away from other horses to prevent the development or progression of lesions (Rashmir-Raven et al. 5. fragmentation and disorientation of collagen fibers in mid to deep dermis (Lerner and McCracken.b).diagcenter. 2006a. 1988. 2007). Owners often report that lesions heal slowly. 7 8 See www. 2007). When using the diagnostic criteria of amylase-resistant abnormal polysaccharide on muscle biopsy samples from suspect horses. however. scars.. as well as thinning. the mode of inheritance is autosomal dominant (McCue et al. 2007). the prevalence of PSSM has been estimated at 36% and 6% in Belgian Draft horses and Quarter Horses. 1991). 2004). Affected horses are often euthanased due to severity of lesions and associated discomfort. respectively (Firshman et al.. 2004..edu. although lesions can be found in other locations associated with trauma.edu. There has been no evidence of collagen-associated abnormalities in any internal organs of affected animals at post-mortem examination (White et al.

McCue et al. The most common clinical signs of PSSM in draft breeds include muscle weakness. Commercialisation of a genetic test for PSSM is underway.. 2007).. Hydration status should be assessed and either oral or intravenous fluids administered if necessary as myoglobin is toxic to the kidneys and persistent dehydration.. a true clinical distinction has not been made between homozygotes versus heterozygotes. Firshman et al. In Warmbloods. respectively. 2006). Fig. Clinical signs of exertional rhabdomyolysis. 1992. personal communication). however.344 C. In draft breeds. Note the numerous fibers with abnormal granular polysaccharide. Sprayberry et al.. stiffness. In Quarter Horses with PSSM.J. . The mutation is a 10 single base-pair substitution in the glycogen synthase 1 gene located on chromosome 10 (McCue et al. serum CK and AST are often normal. 1998). It is important to note that many draft horses with PSSM are asymptomatic. Sedatives and antiinflammatories may be administered to the well-hydrated horse to relieve anxiety and pain. 1997. Hunt et al. The characteristic features in histological sections include the presence of subsarcolemmal vacuoles and the presence of amylase-resistant PAS positive abnormal polysaccharide inclusions in the skeletal muscle fibers (Valberg et al.. including muscle pain. Semimembranosus muscle biopsy from a horse affected with PSSM predigested with amylase to remove all the normal glycogen and then stained with periodic acid Schiff’s stain... 2003).. particularly if the horse has been rested for several days before exercise (Firshman et al. 2006). Diagnosis Persistent elevations of serum creatine kinase and aspartate transaminase (AST) may be seen in Quarter Horses with PSSM. Signs observed less frequently include mild colic.. 2005. the median CK and AST was 323 U/L and 332 U/L. 7. 2008). The median CK and AST activity of all Quarter Horses with PSSM with muscle biopsies submitted to the Neuromuscular Diagnostic Laboratory at the Univer- sity of Minnesota was 2809 and 1792 U/L. The mutation appears to result in unregulated glycogen synthesis and potentially impaired aerobic glycogen metabolism (Valberg and Mickelson. the average age at diagnosis was 8 years (Firshman et al. In Warmbloods. In draft horses and Warmbloods with PSSM. with the hindquarters most frequently affected (Firshman et al.. Finno et al. and muscle fasicultations and exertional rhabdomyolysis which may be so severe that it leads to recumbency and death (Valentine et al.. The median serum CK and AST activity in draft horses from which biopsies were sent to the Neuromuscular Diagnostic Laboratory at the University of Minnesota was 459 and 537 U/L. 2003). 2002. gait abnormalities and muscle atrophy (Quiroz-Rothe et al. 2003). 2005). 2005) and the most common clinical abnormalities include a pain over the back and hindquarter muscles. It is important to note that stall confinement should be limited to <48 h after the episode of rhabdomyolysis as prolonged stall confinement may result in an increased incidence of rhabdomyolysis episodes due to PSSM. exercise intolerance. respectively (Valberg.. a few days of stall confinement may be indicated in horses showing pronounced stiffness or weakness. 1999)... weakness. respectively. failure to round the back over fences. reluctance to collect and engage the hindquarters. The most common trigger for clinical signs of PSSM is <20 min of exercise at a walk and trot. Although the gait abnormality called ‘shivers’ was suggested to be attributable to PSSM (Valentine et al. Treatment For an acute episode. a recent study found both conditions to be highly prevalent but no causal relationship was found between these two conditions (Firshman et al. and reluctance to move may be observed. can result in development of acute renal failure. The eventual accumulation of abnormal polysaccharide in skeletal muscle appears to develop over a period of a few years and the accumulation may not be evident in muscle biopsies from affected horses <2 years of age (De La Corte et al.. Etiology An autosomal dominant mutation in a gene regulating glycogen synthesis has recently been identified in Quarter Horses and draft horses with PSSM (Valberg and Mickelson. 2007). homozygotes generally appear more severely affected (Valberg. 2002). 2005) (Fig. gait abnormalities and muscle wasting. sweating. A definitive diagnosis of PSSM can be made on the evaluation of a muscle biopsy from horses older than 2 years of age. the age of onset of clinical signs is between 8 and 11 years of age (Hunt et al. the average age of onset of clinical signs is 5 years (Firshman et al. gait abnormalities. 7). / The Veterinary Journal 179 (2009) 336–347 Clinical signs In Quarter Horses. 2005).. in addition to myoglobinuria.

recurrent exertional rhabdomyolysis.. Spier. . Byrns. Hoffman.. M... 41–42.. Rashmir-Raven..T. 122–125.A. H. A.. Linkage of the gene for equine combined immunodeficiency disease to microsatellite markers HTG8 and HTG4. Gary Magdesian and Dr.C. 2004. Lecouteur.V.P..au. R. 2003. It has been demonstrated that strict adherence to dietary and exercise recommendations will result in improvement in clinical signs in 54% and 75% of Warmbloods and Quarter Horses. Frequency of the SCID gene among Arabian horses in the USA... Fell Pony immunodefiency.A. Evidence for a single pedigree source of the hyperkalemic periodic paralysis susceptibility gene in quarter horses. 1994.H. B.. S. The objective of increasing the duration of exercise is to augment the capacity of the muscle in to oxidise fat and glycogen as energy substrates. there are many inherited disorders for which a genetic mutation is not yet known. Excessive fat supplementation of 1 lb (0.. Stephan White for providing photographs. Muscle Nerve 30. 2003.I. Bailey.. synteny and FISH mapping to ECA9. K. 268–273..M. / The Veterinary Journal 179 (2009) 336–347 345 Control With adherence to diet and exercise recommendations.. anterior segment dysgenesis. at least 80% of horses show notable improvement in clinical signs. 1996. Williams. Hunt et al.. Prognosis Horses with PSSM will always have an underlying predilection for muscle soreness. Baird. R. E.... Osburn..L. many return to acceptable levels of performance (Firshman et al. Aldridge. 2005). Riehl.J. R. The influence of peptidyl-prolyl cis-trans isomerase on the in vitro folding of type III collagen. Journal of the American Veterinary Medical Association 170. Bailey. Animal Genetics 27.C. Re-evaluating serum CK is not usually helpful in the first month.. A. Pessah.. Dietary management should be aimed at providing adequate. As the field of equine genetics continues to develop. An online catalogue of inherited disorders. Brosnan. M. McGuire. Acknowledgements The authors would like to thank Dr. Trees... It is important to institute both dietary and exercise changes over a period of time (1–4 months) before assessing the horse’s response. L.angis..D. R. D.. and horses may return to a previous level of performance (Firshman et al. and hemophilia A. resulting in graft versus host reaction. E.. J. 363–366. Kortz.. Charlesworth. 1998. A. D.C.A. Decreasing the dietary starch to <10% of daily digestible energy and increasing dietary fat up to 13% of daily digestible energy is recommended (Ribeiro et al. 2005).G. G.G. Animal Genetics 28. 356– 365.. Stabenfeldt. 1997. 2005). Veterinary Dermatology 12... S. pp..D. Spier.. but not excessive.P... S.E. S. 2003. An appropriate exercise regimen following an episode of rhabdomyolysis would be a 2 week period of turnout while the diet is being changed and then a gradual return to exercise. Junctional Epidermolysis Bullosa in Belgian Draft Horses. Meneguzzi. 1987. Cell 79...M. Tharp.. E. L. Steffey. A. M. A. 2001. G. 1977. M. by decreasing the glucose load and providing fat as an alternate energy source. Zonal dermal separation: a distinctive histopathological lesion associated with hyperelastosis cutis in a Quarter Horse. Lear. Lecouteur. Mayhew. A. S.. 1277–1285. lavender foal syndrome. Laryngeal and pharyngeal dysfunction in horses homozygous for hyperkalemic See http://omia.J. E.. Giaid..C. but may be used after that time to monitor any additional muscle damage.A. Sawyer.H. 2004). Finno et al. Baynash. Mathiason. 2006).. Ardans. Malignant hyperthermia in a horse anesthetized with halothane. Conclusions With the complete sequencing of the horse genome and development of equine genome maps. respectively. Aleman. Spirito. 2003. J. J. Yanagisawa. Emoto.org. K. Firshman et al. it is likely that many more loci for single and polygenic traits will be identified. J. a feed that contains >10% of fat by weight and <20% of starch or non-structural carbohydrates by weight (Valberg.C. Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.45 kg) of fat per day may lead to unnecessary weight gain and over time adverse consequences such as metabolic syndrome Pastures and hay with a low non-structural carbohydrate content should be combined with a vitamin mineral supplement and where necessary. entitled ‘Online Mendelian Inheritance in Animals’ is available9 and provides recent information on inherited equine disorders 9 while citing relevant publications. Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia. Immunotherapy in two foals with combined immunodeficiency. Black. LA. T.. 17144–17148. A.R. 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