12
Review 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 b 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 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, treat- ment 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 off- spring are affected, or when developmental, congenital, or lethal traits are involved. The identification of genetic dis- eases has been hampered in horses due to their long gesta- tion, 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 com- parative 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 polysac- charide storage myopathy (PSSM). In addition to simple Mendelian genetic traits, these new technologies will pro- vide 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 autoso- mal 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 muscula- ture and favorable results in shows as superior halter 1090-0233/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.tvjl.2008.03.016 * Corresponding author. Tel.: +1 530 752 0290; fax: +1 530 752 9815. E-mail address: cjfi[email protected] (C.J. Finno). www.elsevier.com/locate/tvjl Available online at www.sciencedirect.com The Veterinary Journal 179 (2009) 336–347 The Veterinary Journal

Equine diseases caused by known genetic mutations

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Page 1: Equine diseases caused by known genetic mutations

Available online at www.sciencedirect.com

www.elsevier.com/locate/tvjl

The Veterinary Journal 179 (2009) 336–347

TheVeterinary Journal

Review

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, USAb 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

Accepted 25 March 2008

Abstract

The recent development of equine genome maps by the equine genome community and the complete sequencing of the horse genomeperformed at the Broad Institute have accelerated the pace of genetic discovery. This review focuses on genetic diseases in the horse forwhich a mutation is currently known, including hyperkalemic periodic paralysis, severe combined immunodeficiency, overo lethal whitesyndrome, junctional epidermolysis bullosa, glycogen branching enzyme deficiency, malignant hyperthermia, hereditary equine regionaldermal asthenia, and polysaccharide storage myopathy. Emphasis is placed on the prevalence, clinical signs, etiology, diagnosis, treat-ment and prognosis for each disease.Published by Elsevier Ltd.

Keywords: Genetics; Mutations; Hereditary; Horse

Introduction

Greater interest will arise in genetic causes of diseasewhen a specific breed is affected, when several related off-spring are affected, or when developmental, congenital, orlethal traits are involved. The identification of genetic dis-eases has been hampered in horses due to their long gesta-tion, single births, dispersion of horses after weaning, andexistence of many diseases with delayed onset of expressionor variable penetrance. Furthermore, there were limitedtools available to study genetic diseases in horses until2006, with advances in this field primarily relying on theoccurrence of homologies in other species, using the com-parative gene approach.

The recent development of equine genome maps by theequine genome community (Spencer and Davis, 2007) andthe complete sequencing of the horse genome performed atthe Broad Institute under the auspices of the NationalHuman Genome Research Institute have accelerated the

1090-0233/$ - see front matter Published by Elsevier Ltd.

doi:10.1016/j.tvjl.2008.03.016

* Corresponding author. Tel.: +1 530 752 0290; fax: +1 530 752 9815.E-mail address: [email protected] (C.J. Finno).

pace of genetic discovery. In 2007, genome mapping wasused to identify two new genetic mutations for hereditaryequine regional dermal asthenia (HERDA) and polysac-charide storage myopathy (PSSM). In addition to simpleMendelian genetic traits, these new technologies will pro-vide the means to identify quantitative trait loci formulti-factorial traits in the near future. This review focuseson the genetic diseases in the horse for which a mutation iscurrently known.

Hyperkalemic periodic paralysis (HYPP)

Hyperkalemic periodic paralysis (HYPP) is an autoso-mal dominant trait affecting Quarter Horses, AmericanPaint Horses, Appaloosas and Quarter Horse crossbredanimals worldwide. The genetic disease has been associatedwith a Quarter Horse sire named Impressive and it hasbeen estimated that 4% of the Quarter Horse breed maybe affected (Bowling et al., 1996). Horses affected by HYPPmay have been preferentially selected as breeding stock dueto their phenotypic expression of well-developed muscula-ture and favorable results in shows as superior halter

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1 See www.vgl.ucdavis.edu.

C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347 337

horses (Naylor, 1994a). In 1996, the American QuarterHorse Association (AQHA) officially recognized HYPPas a genetic defect or undesirable trait and mandatory test-ing for HYPP was instituted, with these results recorded onthe Registration Certificate for all foals that descendedfrom Impressive and were born after January 1, 1998. In2004, the AQHA ruled that foals born in 2007 or laterand that tested homozygous affected for HYPP (H/H)would not be eligible for registration. Horses that testedheterozygous affected for HYPP are designated as N/Hand normal unaffected horses as N/N.

Clinical signs

Clinical signs among horses affected by HYPP rangefrom asymptomatic to daily muscle fasciculations andweakness resulting in recumbency. Episodes of weaknessor paralysis appear similar between N/H and H/H horses,although the H/H will have more frequent episodes andtend to show more severe signs of upper airway obstruc-tion during an episode. Foals homozygous for HYPP usu-ally show clinical signs of disease in the first few days oflife. Clinical signs in H/H foals include respiratory stridorand periodic obstruction of the upper respiratory tract.Foals may present for dysphagia or respiratory distress,and endoscopic findings include pharyngeal collapse andedema, largyngopalatal dislocation and laryngeal paraly-sis (Carr et al., 1996). Affected homozygous horses alsoexhibit dysphonia (high-pitched whinny) even betweenepisodes.

Foals that are heterozygous N/H are less severelyaffected and typically do not demonstrate clinical signs ofdisease until they are weaned. By the time training is initi-ated, typically by 2–3 years of age, most N/H horses haveshown intermittent clinical signs with no apparent abnor-malities between episodes (Spier et al., 1990; Rudolphet al., 1992; Naylor, 1994b). In heterozygous or homozy-gous HYPP horses, clinical episodes begin with a periodof brief hypotonia (twitching or delayed relaxation of mus-cles), with some horses showing prolapse of the third eye-lid. Sweating and muscle fasiculations are observedcommonly in the flanks, neck and shoulders. Stimulationand attempts to move may exacerbate muscle tremorsand some horses develop severe muscle cramping. Duringmild attacks, horses remain standing. In more severeattacks, clinical signs may progress to swaying, staggering,dog-sitting, or recumbency within a few min. Horses maybe tachycardic and tachypneic during episodes, yet remainrelatively bright and alert. Episodes last for variable peri-ods, usually 15–60 min. Several horses have died duringacute episodes (Cox, 1985). Respiratory distress, due toparalysis of upper respiratory muscles, can occur in eitherH/H or N/H animals and may require a tracheostomy.

After an episode of HYPP subsides, horses appear nor-mal. Electromyographic examination of asymptomaticHYPP horses reveals abnormal fibrillation potentials, com-plex repetitive discharges with occasional myotonic poten-

tials and trains of doublets between episodes (Spier et al.,1990; Naylor, 1994b).

Episodes of HYPP are often triggered by diets contain-ing >1.1% of potassium in the total daily intake on a dryweight basis. Feeds high in potassium include alfalfa hay,molasses, electrolyte supplements and kelp-based supple-ments (Reynolds et al., 1998). Other precipitating factorsinclude fasting, anesthesia or heavy sedation, trailer ridesand stress (Spier, 2006). Exercise does not appear to induceclinical signs and serum creatine kinase (CK) shows nochange or a very modest increase during episodic fascicula-tions and weakness.

Etiology

HYPP is due to a missense mutation (C to G substitu-tion) resulting in a phenylalanine/leucine substitution inthe alpha-subunit of the voltage-dependent skeletal mus-cle sodium channel alpha-subunit (SCN4A) (Rudolphet al., 1992). The SCN4A gene was mapped to chromo-some 11 at 14247699–14275289 (University of CaliforniaSanta Cruz, 2008). In horses with HYPP, the restingmembrane potential is closer to firing than in normalhorses (Pickar et al., 1991). Sodium channels are nor-mally briefly activated during the initial phase of the mus-cle-action potential. The HYPP mutation results in afailure of a subpopulation of sodium channels to inacti-vate when serum-potassium concentrations are increased.As a result, an excessive inward flux of sodium and out-ward flux of potassium ensues, resulting in persistentdepolarization of muscle cells followed by temporaryweakness.

Diagnosis

Descendents of the stallion Impressive on the sire ordam’s side in a horse with episodic muscle tremors, weak-ness, or collapse is strongly suggestive of HYPP. However,as other diseases can produce similar signs (e.g. myotonia,exertional rhabdomyolysis, neurologic disorders, electro-lyte derangements) and veterinarians may not be presentduring acute episodes, the definitive test for identifyingHYPP is the demonstration of the base-pair sequence sub-stitution in SCN4A (Rudolph et al., 1992). Submission ofmane or tail hair with roots should be made to a licensedlaboratory such as the Veterinary Genetics Laboratory atthe University of California at Davis.1 The test for HYPPclearly differentiates between H/H, N/H or N/N horses(homozygous affected, heterozygous affected, or normal,respectively) (Fig. 1).

In most cases, hyperkalemia (6–9 mEq/L), hemoconcen-tration, and mild hyponatremia occur during clinical man-ifestations of the disease with normal acid-base balance(Spier et al., 1990). Serum-potassium concentration returns

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Fig. 1. DNA test for HYPP from the Veterinary Genetics Laboratory,University of California, Davis. The alleles are HYPP-N (normal) andHYPP-H (affected). Each sample is amplified with two pair of primers foran internal control of the PCR test.

338 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347

to normal after the cessation of clinical signs. Some affectedhorses may have normal serum-potassium concentrationsduring minor episodes of muscle fasciculations (Naylor,1994b).

Treatment

Light exercise when clinical signs are first observed cansometimes abort an episode in mild cases. Feeding grainor corn syrup to stimulate insulin-mediated movement ofpotassium across cell membranes may be of benefit. Othertreatment options include administration of epinephrine(3 mL of 1:1000/500 kg intramuscularly [IM]) and adminis-tration of acetazolamide (3 mg/kg every 8–12 h orally[(PO]). Many horses spontaneously recover from episodesof paralysis and may appear normal by the time a veteri-narian arrives.

In severe cases, administration of calcium gluconate(0.2–0.4 mL/kg of a 23% solution diluted in 1 L of 5% dex-trose) will often provide immediate improvement. Anincrease in extracellular calcium concentration raises themuscle-membrane threshold potential, which attenuatesmembrane hyperexcitability. To reduce serum potassium,IV dextrose (6 mL/kg of a 5% solution) alone or combinedwith sodium bicarbonate (1–2 mEq/kg) can be used toenhance intracellular movement of potassium. With severedyspnea due to laryngeal or pharyngeal obstruction, a tra-cheostomy may be necessary.

Control

Decreasing dietary potassium and increasing renal lossesof potassium are the primary steps taken to prevent HYPPepisodes. Regular exercise and frequent turnout are benefi-cial. Horses with HYPP can graze pastures because thehigh water content of the pasture grass makes it unlikely

that horses will consume large amounts of potassium in ashort time. Ideally, horses with recurrent episodes of HYPPshould be fed a balanced diet containing between 0.6% and1.1–1.5% total potassium concentration and meals contain-ing <33 g of potassium (Reynolds et al., 1998). For horseswith recurrent episodes of muscle fasiculations even afterdietary alterations are instituted, acetazolamide (2–3 mg/kg every 8–12 h PO) or hydrochlorothiazide (0.5–1 mg/kgevery 12 h PO) may be helpful. These agents exert theireffects through different mechanisms, although both inducean increase in renal potassium ATPase activity (Cox, 1985).In addition, acetazolamide stabilises blood glucose andpotassium by stimulating insulin secretion. Breed registriesand other associations have restrictions on the use of thesedrugs during competitions.

Prognosis

In most cases, HYPP is manageable disorder, althoughrecurrent bouts may occur and severe episodes can be fatal.Owners of affected horses should be strongly discouragedfrom breeding these animals. Since HYPP is a dominanttrait, breeding a heterozygous affected horse (N/H) to anormal horse (N/N) results in a 50% chance of producinga foal heterozygous for HYPP, while breeding a homozy-gous affected horse (H/H) to a normal horse (N/N) resultsin a 100% chance of producing a heterozygous affectedhorse (N/H). All affected horses share the same mutation,regardless of whether or not owners have witnessed clinicalsigns in their horses (Zhou et al., 1994). Owners of affectedhorses should advise veterinarians of HYPP status beforeanesthesia or procedures requiring heavy sedation. Horsesdescended from Impressive should be tested for HYPP dur-ing pre-purchase examination.

Severe combined immunodeficiency (SCID)

Severe combined immunodeficiency (SCID) is an auto-somal recessive trait reported in Arabian horses. Affectedfoals have been identified in Australia, Canada, Great Brit-ain and the United States (McGuire and Poppie, 1973;Clark et al., 1978; Studdert, 1978; Whitwell, 1978). The fre-quency of SCID gene carriers among Arabian horses in theUnited States was estimated at 8.4% and, based upon thisfrequency, 0.18% of Arabian foals would be expected to behomozygous for the gene (Bernoco and Bailey, 1998).

Clinical signs

Affected foals are clinically normal at birth as passivetransfer confers protective immunity, but foals are thenmore susceptible to infectious disease and normally suc-cumb by 5 months of age. The age of onset of infectiondepends on the adequacy of passive transfer and the envi-ronmental challenge, but usually occurs by 6–10 weekspost-partum. Diseases of the respiratory tract are common,caused most frequently by adenovirus or Pneumocystis

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Fig. 2. A frame overo Paint Horse.

C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347 339

carinii (McGuire et al., 1974; Perryman et al., 1978; Studd-ert, 1978), frequently accompanied by secondary bacterialinfection (McGuire and Poppie, 1973; Perryman et al.,1978; Studdert, 1978). Intermittent diarrhea may also beobserved (Studdert, 1978). Additional lesions include hepa-tic necrosis with biliary hyperplasia, ulcerative enteritis,focal myocardial necrosis, peritonitis, pleuritis and pericar-ditis (Perryman et al., 1978). Meningitis caused by listerio-sis has been documented in a SCID foal (Clark et al.,1978).

Etiology

The genetic defect responsible for SCID is a five-base-pair deletion (frameshift mutation) at codon 9480 resultingin a frameshift mutation and a 967 amino acid deletionfrom the C terminus, including the entire PI3 kinasedomain, and an unstable mutant protein in the gene encod-ing the DNA-protein kinase catalytic subunit (DNA-PKcs)(Shin et al., 1997a; University of California Santa Cruz,2008). The gene is located on chromosome 9 (Baileyet al., 1997).

During early lymphoid differentiation, distinct gene seg-ments called variable (V), diversity (D) and joining (J),combine to form coding sequences of immunoglobulinand T-cell antigen receptor variable regions. This V(D)Jrecombination is necessary for differential expression ofantigen receptors on B and T lymphocytes. Foals withSCID have a 967 amino acid deletion in the enzymeDNA-dependent protein kinase, which is required forV(D)J recombination and for repair in the double-strandedDNA breaks (Wiler et al., 1995). This deletion in the cata-lytic subunit of the DNA-PK causes DNA-PK to be inac-tive (Shin et al., 1997b). Affected foals lack both B and Tlymphocytes and therefore lack an endogenous humoralor cell-mediated response.

Diagnosis

Prior to the discovery of the genetic mutation, diagnosisof SCID was based on absolute lymphopenia (<1000/lL),lymphoid hypoplasia on lymph node histopathology, theabsence of immunoglobulin M (IgM) in the pre-suckleserum and complete absence of germinal centers in lym-phoid tissue and thymic hypoplasia at post-mortem exam-ination (McGuire and Poppie, 1973; Studdert, 1978).Definitive diagnosis is based upon identification of theDNA-PKcs gene deletion in hair or blood samples throughvetGen (www.vetgen.com).

Treatment

Supportive care may prolong the course of disease, butaffected foals eventually die by 5 months. For research pur-poses, foals with SCID have been treated with twice weeklyIV administration of plasma hyperimmunised with anti-adenovirus antibody and these foals have lived up to 11

months of age (Perryman et al., 1978). In most cases, bonemarrow transplantation and thymus transplantation havebeen unsuccessful, with no evidence of immunoglobulinproduction at the time of death (Ardans et al., 1977). How-ever, immunologic reconstitution was completed in oneSCID foal that was transplanted with 1.8 � 108 viable bonemarrow cells/kg bodyweight (BW) that had been obtainedfrom a histocompatible full sibling donor (Perryman et al.,1987). This foal was monitored for 650 days and immuno-logic reconstitution remained complete. Treatment is notrecommended and affected foals should be euthanased.

Control and prognosis

Genetic testing of breeding Arabians is recommended.Prognosis for affected foals is invariably grave.

Ileocolonic aganglionosis (overo lethal white foal syndrome)

Ileocolonic aganglionosis, or overo lethal white foal syn-drome (OLWS), is an autosomal recessive trait affectingfoals of American Paint Horse, Quarter Horse and, rarely,Thoroughbred breeds. The disorder has also been referredto as aganglionic megacolon (McCabe et al., 1990) and isthe equine variant of Hirschsprung disease, a disorderaffecting humans (Metallinos et al., 1998; Yang et al.,1998). Breeding of carriers of OLWS may produce foalsthat are all white or nearly all white and die from colicshortly after birth due to functional intestinal obstruction.Some affected foals may have flecks of black hair in themain, tail or a small black body spot.

A very high incidence (>94%) of OLWS heterozygotes isfound in frame overo (Fig. 2), highly white calico overoand frame blend overo (Santschi et al., 2001). Whitecoat-colored patterns with a low incidence of OLWS het-erozygotes (<21%) include tobiano (Fig. 3), sabino, mini-mally blend overo, and breeding-stock solid (Santschiet al., 2001). It is important to note, however, that the

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Fig. 3. A tobiano Paint Horse.

340 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347

many solid (non-white coat color pattern) horses withPaint horse bloodlines are heterozygous and therefore thegenotype can not necessarily be inferred from coat colorpatterns (Metallinos et al., 1998).

Clinical signs

Overo lethal white foal syndrome is characterised by awhite coat and intestinal tract abnormalities that result incolic and related signs within 12 h of birth (Vonderfechtet al., 1983). The colic is not responsive to analgesics andprogressive abdominal distension will be seen with no fecalmaterial passed. The intestinal abnormalities are due to thecomplete absence of intrinsic myenteric plexus in the termi-nal small intestine, cecum and entire colon, with the ileummost severely affected (Hultgren, 1982; Vonderfecht et al.,1983).

Embryologically, both melanocytes and myenteric gan-glia cells are of neural crest origin and their failure tomigrate from the neural crest results in the absence of mel-anocytes in the skin and aganglionosis of the intestine(Hultgren, 1982). Some foals may be deaf and have blueeyes in addition to the pigment defects and aganglionosis(Vonderfecht et al., 1983; McCabe et al., 1990). Foals thathave all white coat color patterns do not inexorably haveOLWS. Dominant white color patterns, albinos and somefoals heterozygous for OLWS may have all white coatswithout aganglionosis.

2 See www.vgl.ucdavis.edu.

Etiology

The genetic defect responsible for OLWS is a singlebase-pair change (missense mutation) resulting in a isoleu-cine/lysine substitution at codon 118 of the endothelinreceptor B (EDNRB) gene located on chromosome 17 at49432374–49454137 (University of California Santa Cruz,2008). Affected foals are homozygous for the Lys gene(Lys 118/Lys 118) and carriers are heterozygous (Ile 118/

Lys 118) (Santschi et al., 1998). The equine Ile to Lys

EDNRB substitution is in transmembrane domain one ofa seven transmembrane domain G-protein coupled recep-tor for the endothelins. Both endothelin B receptor andendothelin 3 are essential for normal development of theenteric ganglia and melanocytes within the neural crest(Baynash et al., 1994; Hosoda et al., 1994).

Diagnosis

A white foal with signs of colic that does not pass anymeconium is almost pathognomonic for the disease,although radiographs, contrast studies and an ultrasoundexamination may be indicated to diagnose complete bowelobstruction. White Paint foals without evidence of colicmay not be homozygous for the OLWS mutation andshould be genetically tested. The genetic test is also usefulto determine carrier status, especially for non-frame over-os, tobianos, and out-cropped Quarter Horses (horses withwhite color markings). Testing is available through the Vet-erinary Genetics Laboratory at the University of Californiaat Davis.2

Treatment and prognosis

There is no treatment available and the prognosis isinvariably grave.

Junctional epidermolysis bullosa (JEB)

Junctional epidermolysis bullosa is an autosomal reces-sive trait affecting Belgians, other draft breeds and Ameri-can Saddlebred horses (Frame et al., 1988; Kohn et al.,1989; Lieto et al., 2002; Milenkovic et al., 2003). The dis-ease has also been referred to as equine epitheliogenesisimperfecta or hereditary junctional mechanobullous dis-ease. A mutation causing JEB has been identified in Bel-gian horses. In North America, 17% of Belgian horseswere carriers of the mutation and in Europe, 8–27% ofhorses of the Breton, Comtois, Vlaams Paard, and Belgi-sche Koudbloed Flander draft horse breeds were carriers(Baird et al., 2003). The draft horse JEB mutation wasnot identified in a screening of 107 American Saddlebreds.

Clinical signs

Foals are typically born alive, but irregular, reddenederosions and ulcerations develop in the skin and mouthover pressure points or after mild trauma (Shapiro andMcEwen, 1995). Since the skin is so fragile, intact bullaeare rarely seen and blisters are commonly noted (Knotten-belt et al., 2004). Extensive erosions may be present atmucocutaneous junctions of the mouth, rectum and vulva,and along the coronary bands. Granulation tissue along

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C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347 341

the coronary bands may result in separation of the coro-nary bands from the hoof wall and sloughing of the hooves(Kohn et al., 1989). Corneal ulcers and dystrophic teeth arealso described (Shapiro and McEwen, 1995). The foal mayhave temporary incisor teeth visible at birth that are whitewith irregular serrated edges and pitted enamel (Bairdet al., 2003). Secondary bacterial infections, scarring,impaired alimentation due to oral lesions and death usuallyfollow (Johnson et al., 1988).

Etiology

The genetic defect responsible for JEB in the Belgianand European draft breeds is a cytosine insertion(1368insC) creating a premature stop codon in the Lamc2gene, which encodes the laminin c2 subunit chain (Spiritoet al., 2002). The Lamc2 gene is located on chromosome5 at 108228152–108279653 (University of California SantaCruz, 2008). The truncated laminin c2 subunit chains lacksthe C-terminal domain so it cannot interact with the othertwo subunits thereby preventing the formation of laminin 5(Spirito et al., 2002). Laminin 5 is widely distributed in thebasement membrane of epithelial tissues. The absence oflaminin 5 results in a cleft between the basement membranezone of the dermal-epidermal junction, which is evident onmicroscopic evaluation of skin biopsies from affected foals(Johnson et al., 1988). The mutation for JEB in AmericanSaddlebreds has not been identified but is suspected toinvolve the LAM a3 gene (Lieto, 2001) located on chromo-some 8 (Milenkovic et al., 2002). In Saddlebreds the clinicalpresentation has been compared to epitheliogenesis imper-fecta (Lieto et al., 2002).

Diagnosis

A high index of suspicion is raised by typical clinicalsigns combined with skin biopsy findings of separation ofthe epidermis from the dermis by subepidermal clefts thatare relatively free of inflammatory cells and debris (John-son et al., 1988). Definitive diagnosis in draft horsesrequires DNA testing for JEB.3

Treatment and prognosis

There is no treatment for affected foals and they willeventually succumb to secondary infections or completesloughing of the hooves.

Glycogen branching enzyme deficiency (GBED)

Glycogen branching enzyme deficiency (GBED) is anautosomal recessive disease affecting Quarter Horse andPain Horse breeds. Carrier frequency estimates of 7.1%

3 See www.vgl.ucdavis.edu.

and 8.3% in the Paint and Quarter horse breeds, respec-tively, have recently been reported (Wagner et al., 2006).

Clinical signs

Many affected foals may be aborted or stillborn (Renderet al., 1999; Valberg et al., 2001; Wagner et al., 2006). If thefoal survives to term, it may appear weak and hypothermicat birth and may progress to sudden death following hypo-glycemic seizures, cardiac arrest or respiratory failure (Val-berg et al., 2001; Valberg and Mickelson, 2006). Affectedfoals may have flexural limb deformities. All affected foalsstudied to date have died or been euthanased by 18 weeksof age due to the severity of muscle weakness (Valberg andMickelson, 2006).

Etiology

GBED is due to a C to A point mutation at base 102that results in a stop codon in exon 1 of the GBE1 geneencoding glycogen branching enzyme (Ward et al., 2004).The GBE1 gene was mapped to equine chromosome 26at 33459264–33657117 (University of California SantaCruz, 2008). Glycogen is a required energy source in therapidly growing fetus and neonate and is synthesized byglycogen synthase, which creates straight chains of glucosewith alpha 1,4-glycosidic linkages and by glycogen branch-ing enzyme, which creates a branched structure throughalpha 1,6-linkages. Tissues from GBED foals have no mea-surable GBE-enzyme activity or immuno-detectable GBEand cannot form normally branched glycogen (Valberget al., 2001). As a result, cardiac and skeletal muscle, liverand the brain cannot store or mobilise glycogen to main-tain normal glucose homeostasis.

Diagnosis

Common hematologic findings include a leucopenia andmoderate elevations in serum creatine kinase, aspartatetransaminase and gamma glutamyl transferase (Valberget al., 2001). Skeletal muscle, Purkinje cells or cardiac myo-cytes may contain basophilic globules and eosinophiliccrystalline material in hematoxylin and eosin stains (Val-berg et al., 2001; Wagner et al., 2006). Periodic acid Schiff’s(PAS) stains are required for a histopathological diagnosisas they clearly show PAS positive globular inclusions withdecreased normal background staining for glycogen in car-diac and skeletal muscle (Valberg et al., 2001) (Fig. 4).Definitive diagnosis requires identification of the mutationin GBE1 by the University of California Veterinary Genet-ics Laboratory4 or Vet Gen,5 which are both licensed bythe University of Minnesota to perform the test. Mane ortail hairs with roots intact or fetal liver tissue can be sub-

4 See www.vgl.ucdavis.edu.5 See www.vetgen.com.

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Fig. 4. Semimembranosus muscle biopsy from a foal affected with GBEDstained with Periodic Acid Schiff’s stain. Note the little normal back-ground staining for glycogen and accumulation of large globular as well assmaller crystalline inclusions of polysaccharide.

6 See www.vgl.ucdavis.edu.

342 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347

mitted to determine if horses are affected or carriers ofGBED.

Treatment and prognosis

There is no treatment for GBED and the prognosis isgrave. It is important to test aborted foals and stillbornsfor this disease or to test the dams for carrier status.

Malignant hyperthermia

Etiology

An autosomal dominant mutation has been identified intwo Quarter Horses that developed marked hyperthermiaand metabolic acidosis during inhalation anesthesia (Ale-man et al., 2004, 2005). Both horses were homozygousfor a mutation in exon 46 of the skeletal muscle ryanodinereceptor gene (RYR1). The prevalence of the RYR1 muta-tion in Quarter Horses is not known at this time. It is notassociated with recurrent exertional rhabdomyolysis(Dranchak et al., 2006).

Clinical signs

One horse developed hyperthermia during an experi-mental protocol in which anesthesia was induced by deliv-ering halothane via a face-mask without premedication(Aleman et al., 2005). After approximately 60 min of anes-thesia, the horse’s PaCO2 and rectal temperature rose pre-cipitously despite an increase in minute ventilation. At theend of anesthesia, the body temperature was 40.5 �C(104.9 �F), while a PaCO2 of 274 mmHg and a blood pHof 6.72 were recorded. The horse died of cardiopulmonaryarrest and profound rigor mortis was present almost imme-diately. Hematologic changes measured 2 min after deathincluded hemoconcentration, hyperkalemia, hypercalce-mia, hyperphosphatemia, hyperglycemia and elevated cre-atinine. Serum CK activity was mildly elevated at 843 U/

L and myogobin was 10� higher than the reference range.Muscle biopsy revealed mild myopathic changes including,increased variation in fiber sizes, centrally located nuclei,fiber necrosis, glycogen depletion and ringbinden fibers.

Diagnosis

Classic episodes of malignant hyperthermia are diag-nosed based on clinical signs of lactic acidosis and hyper-thermia >40 �C under halothane anesthesia or followingsuccinylcholine injection. Based on the discovery of agenetic mutation in two Quarter Horses, a PCR basedgenetic test is now available.6 It is not known whether thismutation is present in all horses that develop malignanthyperthermia or whether there may be other yet unidenti-fied mutations that cause signs of hyperthermia and meta-bolic acidosis during anesthesia.

Treatment and control

The most successful outcome for a horse with suspectedmalignant hyperthermia would be pretreatment with oraldantrolene (4 mg/kg) 30–60 min prior to anesthesia (Valv-erde et al., 1990a; Hennig and Court, 1991). There is nocost effective means to deliver dantrolene to horses IV oncean episode has begun. Other means to address hyperther-mia and acidosis include external application of alcohol,fans, chilled intravenous fluids with sodium bicarbonateand mechanical ventilation. Unfortunately, once a fulmin-ant episode is underway it is difficult to prevent cardiacarrest.

Hereditary equine regional dermal asthenia (hyperelastosis

cutis)

Hereditary equine regional dermal asthenia (HERDA),also known as hyperelastosis cutis, is an autosomal reces-sive trait affecting Quarter Horses and horses with Quarterhorse lineage. The disease has been compared to EhlersDanlos syndrome in humans (Hardy et al., 1988). Carrierfrequency has been recently estimated at 3.5% (Tryonet al., 2007), with previous estimates ranging from 1.8%to 6.5% (Tryon et al., 2005). Males and females are affectedequally (White et al., 2004). The prevalence of HERDA ishigher in cutting horses and cow horses.

Clinical signs

Clinical signs of HERDA do not typically appear untilhorses are, on average, 1.5 years of age and is frequentlyassociated with initial saddling or trauma (Rashmir-Ravenet al., 2004; Tryon et al., 2005, 2007; White et al., 2007).Horses affected with HERDA may present with seromasor hematomas, open wounds or sloughing skin (Fig. 5),

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Fig. 5. Phenotype of HERDA-affected horses. Note the extensible skin inaffected tissue that can be easily separated from underlying fascia.

Fig. 6. Phenotype of HERDA-affected horses. A large hematomadeveloped at approximately 1.5 years of age along the dorsum of thisaffected horse.

7 See www.vgl.ucdavis.edu.8 See www.diagcenter.vet.cornell.edu.

C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347 343

loose easily tented skin that does not return to its originalposition (Fig. 6), scars, and white hairs at areas of hair re-growth (White et al., 2004). Affected areas are located pri-marily along the dorsum, although lesions can be found inother locations associated with trauma. Owners oftenreport that lesions heal slowly. There has been no evidenceof collagen-associated abnormalities in any internal organsof affected animals at post-mortem examination (Whiteet al., 2004, 2007).

Etiology

The genetic defect responsible for HERDA initiallylocalized to equine chromosome 1 and subsequently a Gto A substitution at codon 115 was identified in equinecyclophilin B (PPIB) (Tryon et al., 2007). This gene likelyplays a role in the protein folding of collagens (Bachinger,1987; Steinmann et al., 1991), however, the exact means bywhich the recently discovered mutation causes disease isunknown.

Diagnosis

Histological examination of skin biopsies was used as ameans to diagnose HERDA prior to the development ofthe genetic test however samples from grossly normal skinare not helpful in distinguishing HERDA-affected horsesfrom those not affected (Rashmir-Raven et al., 2004; Whiteet al., 2004, 2007). Commonly observed histologicalchanges on skin biopsies include thinning of the dermis,as well as thinning, fragmentation and disorientation ofcollagen fibers in mid to deep dermis (Lerner and McCrac-ken, 1978; Hardy et al., 1988; Stannard, 2000; White et al.,2004). A distinctive horizontal linear zone in which separa-tion of the collagen bundles resulted in the formation of alarge empty cleft between the upper and lower regions ofthe deep dermis has been described in two HERDA cases(Brounts et al., 2001; White et al., 2004). A genetic test

to screen for the mutation is available through the Univer-sity of California at Davis7 and Cornell University.8

Treatment and prognosis

Currently, there is no effective therapy for HERDA.Horses appear less likely to develop lesions during the win-ter and it has been suggested to keep horses indoors andaway from other horses to prevent the development or pro-gression of lesions (Rashmir-Raven et al., 2004). Affectedhorses are often euthanased due to severity of lesions andassociated discomfort.

Polysaccharide storage myopathy (PSSM)

Polysaccharide storage myopathy (PSSM) is a glyco-gen storage disorder affecting Quarter horses, AmericanPaint Horses, Appaloosas, Warmbloods and draft breeds.The acronyms EPSM and EPSSM have also been usedfor this condition. In Quarter Horse and Quarter Horserelated breeds, the mode of inheritance is autosomaldominant (McCue et al., 2006a,b). When using the diag-nostic criteria of amylase-resistant abnormal polysaccha-ride on muscle biopsy samples from suspect horses, theprevalence of PSSM has been estimated at 36% and 6%in Belgian Draft horses and Quarter Horses, respectively(Firshman et al., 2005; McCue et al., 2006). In Warmblo-ods, PSSM appears to be a common disorder with almost50% of muscle biopsies from Warmblood horses beingdiagnosed with PSSM (McCue et al., 2006b). The trueprevalence within the various Warmblood breeds hasnot been studied. PSSM is rarely identified in Arabiansand Thoroughbreds.

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Fig. 7. Semimembranosus muscle biopsy from a horse affected with PSSMpredigested with amylase to remove all the normal glycogen and thenstained with periodic acid Schiff’s stain. Note the numerous fibers withabnormal granular polysaccharide.

344 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347

Clinical signs

In Quarter Horses, the average age of onset of clinicalsigns is 5 years (Firshman et al., 2003). The most commontrigger for clinical signs of PSSM is <20 min of exercise at awalk and trot, particularly if the horse has been rested forseveral days before exercise (Firshman et al., 2003). Clini-cal signs of exertional rhabdomyolysis, including musclepain, stiffness, sweating, exercise intolerance, weakness,and reluctance to move may be observed, with the hind-quarters most frequently affected (Firshman et al., 2003).Signs observed less frequently include mild colic, gaitabnormalities and muscle wasting.

In Quarter Horses with PSSM, a true clinical distinctionhas not been made between homozygotes versus heterozyg-otes; however, homozygotes generally appear moreseverely affected (Valberg, personal communication). Indraft breeds, the average age at diagnosis was 8 years(Firshman et al., 2005). It is important to note that manydraft horses with PSSM are asymptomatic. The most com-mon clinical signs of PSSM in draft breeds include muscleweakness, gait abnormalities, and muscle fasicultations andexertional rhabdomyolysis which may be so severe that itleads to recumbency and death (Valentine et al., 1997;Sprayberry et al., 1998).

Although the gait abnormality called ‘shivers’ was sug-gested to be attributable to PSSM (Valentine et al.,1999), a recent study found both conditions to be highlyprevalent but no causal relationship was found betweenthese two conditions (Firshman et al., 2005). In Warmblo-ods, the age of onset of clinical signs is between 8 and 11years of age (Hunt et al., 2005) and the most common clin-ical abnormalities include a pain over the back and hind-quarter muscles, reluctance to collect and engage thehindquarters, failure to round the back over fences, gaitabnormalities and muscle atrophy (Quiroz-Rothe et al.,2002; Hunt et al., 2005; McCue et al., 2006).

Etiology

An autosomal dominant mutation in a gene regulatingglycogen synthesis has recently been identified in QuarterHorses and draft horses with PSSM (Valberg and Mickel-son, 2007). The mutation is a 10 single base-pair substitu-tion in the glycogen synthase 1 gene located onchromosome 10 (McCue et al., 2008). The mutationappears to result in unregulated glycogen synthesis andpotentially impaired aerobic glycogen metabolism (Valbergand Mickelson, 2007).

Diagnosis

Persistent elevations of serum creatine kinase and aspar-tate transaminase (AST) may be seen in Quarter Horseswith PSSM. The median CK and AST activity of all Quar-ter Horses with PSSM with muscle biopsies submitted tothe Neuromuscular Diagnostic Laboratory at the Univer-

sity of Minnesota was 2809 and 1792 U/L, respectively.In draft horses and Warmbloods with PSSM, serum CKand AST are often normal. The median serum CK andAST activity in draft horses from which biopsies were sentto the Neuromuscular Diagnostic Laboratory at the Uni-versity of Minnesota was 459 and 537 U/L, respectively.In Warmbloods, the median CK and AST was 323 U/Land 332 U/L, respectively (Valberg, 2006).

A definitive diagnosis of PSSM can be made on the eval-uation of a muscle biopsy from horses older than 2 years ofage. The characteristic features in histological sectionsinclude the presence of subsarcolemmal vacuoles and thepresence of amylase-resistant PAS positive abnormal poly-saccharide inclusions in the skeletal muscle fibers (Valberget al., 1992; Firshman et al., 2005) (Fig. 7). The eventualaccumulation of abnormal polysaccharide in skeletal mus-cle appears to develop over a period of a few years and theaccumulation may not be evident in muscle biopsies fromaffected horses <2 years of age (De La Corte et al.,2002). Commercialisation of a genetic test for PSSM isunderway.

Treatment

For an acute episode, a few days of stall confinementmay be indicated in horses showing pronounced stiffnessor weakness. Hydration status should be assessed andeither oral or intravenous fluids administered if necessaryas myoglobin is toxic to the kidneys and persistent dehy-dration, in addition to myoglobinuria, can result in devel-opment of acute renal failure. Sedatives and anti-inflammatories may be administered to the well-hydratedhorse to relieve anxiety and pain. It is important to notethat stall confinement should be limited to <48 h afterthe episode of rhabdomyolysis as prolonged stall confine-ment may result in an increased incidence of rhabdomyol-ysis episodes due to PSSM.

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Control

With adherence to diet and exercise recommendations,at least 80% of horses show notable improvement in clini-cal signs; many return to acceptable levels of performance(Firshman et al., 2003; Hunt et al., 2005). An appropriateexercise regimen following an episode of rhabdomyolysiswould be a 2 week period of turnout while the diet is beingchanged and then a gradual return to exercise, with succes-sive addition of 2 min intervals of walk and trot beginningwith only 4 min of exercise and working up to 30 min after3 weeks (Valberg et al., 1997; Firshman et al., 2003; Huntet al., 2005). Re-evaluating serum CK is not usually helpfulin the first month, as it is often elevated, but may be usedafter that time to monitor any additional muscle damage.The objective of increasing the duration of exercise is toaugment the capacity of the muscle in to oxidise fat andglycogen as energy substrates.

Dietary management should be aimed at providing ade-quate, but not excessive, calories, by decreasing the glucoseload and providing fat as an alternate energy source.Decreasing the dietary starch to <10% of daily digestibleenergy and increasing dietary fat up to 13% of daily digest-ible energy is recommended (Ribeiro et al., 2004). Excessivefat supplementation of 1 lb (0.45 kg) of fat per day maylead to unnecessary weight gain and over time adverse con-sequences such as metabolic syndrome Pastures and haywith a low non-structural carbohydrate content should becombined with a vitamin mineral supplement and wherenecessary, a feed that contains >10% of fat by weightand <20% of starch or non-structural carbohydrates byweight (Valberg, 2006).

Prognosis

Horses with PSSM will always have an underlying pre-dilection for muscle soreness. It is important to instituteboth dietary and exercise changes over a period of time(1–4 months) before assessing the horse’s response. It hasbeen demonstrated that strict adherence to dietary andexercise recommendations will result in improvement inclinical signs in 54% and 75% of Warmbloods and QuarterHorses, respectively, and horses may return to a previouslevel of performance (Firshman et al., 2003; Hunt et al.,2005).

Conclusions

With the complete sequencing of the horse genome anddevelopment of equine genome maps, the discovery ofequine genetic mutations will continue to expand. Anonline catalogue of inherited disorders, entitled ‘OnlineMendelian Inheritance in Animals’ is available9 and pro-vides recent information on inherited equine disorders

9 See http://omia.angis.org.au.

while citing relevant publications. Currently, there aremany inherited disorders for which a genetic mutation isnot yet known, including cerebellar abiotrophy, lavenderfoal syndrome, Fell Pony immunodefiency, anterior seg-ment dysgenesis, recurrent exertional rhabdomyolysis,and hemophilia A. As the field of equine genetics continuesto develop, it is likely that many more loci for single andpolygenic traits will be identified.

Conflict of interest statement

None of the authors of this paper has a financial or per-sonal relationship with other people or organisations thatcould inappropriately influence or bias the content of thepaper.

Acknowledgements

The authors would like to thank Dr. Gary Magdesianand Dr. Stephan White for providing photographs.

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