Available online at www.sciencedirect.

com

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

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 pace of genetic discovery. In 2007, genome mapping was

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
*
Corresponding author. Tel.: +1 530 752 0290; fax: +1 530 752 9815.
E-mail address: cjfinno@vmth.ucdavis.edu (C.J. Finno).
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
 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
horses (Naylor, 1994a). In 1996, the American Quarter
Horse Association (AQHA) officially recognized HYPP
as a genetic defect or undesirable trait and mandatory test-
ing for HYPP was instituted, with these results recorded on
the Registration Certificate for all foals that descended
from Impressive and were born after January 1, 1998. In
2004, 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. Horses that tested
heterozygous affected for HYPP are designated as N/H
and normal unaffected horses as N/N.
Clinical signs
Clinical signs among horses affected by HYPP range
from asymptomatic to daily muscle fasciculations and
weakness resulting in recumbency. Episodes of weakness
or paralysis appear similar between N/H and H/H horses,
although the H/H will have more frequent episodes and
tend 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 of
life. Clinical signs in H/H foals include respiratory stridor
and periodic obstruction of the upper respiratory tract.
Foals may present for dysphagia or respiratory distress,
and endoscopic findings include pharyngeal collapse and
edema, largyngopalatal dislocation and laryngeal paraly-
sis (Carr et al., 1996). Affected homozygous horses also
exhibit dysphonia (high-pitched whinny) even between
episodes.
Foals that are heterozygous N/H are less severely
affected and typically do not demonstrate clinical signs of
disease until they are weaned. By the time training is initi-
ated, typically by 2–3 years of age, most N/H horses have
shown intermittent clinical signs with no apparent abnor-
malities between episodes (Spier et al., 1990; Rudolph
et al., 1992; Naylor, 1994b). In heterozygous or homozy-
gous HYPP horses, clinical episodes begin with a period
of brief hypotonia (twitching or delayed relaxation of mus-
cles), with some horses showing prolapse of the third eye-
lid. Sweating and muscle fasiculations are observed
commonly in the flanks, neck and shoulders. Stimulation
and attempts to move may exacerbate muscle tremors
and some horses develop severe muscle cramping. During
mild attacks, horses remain standing. In more severe
attacks, clinical signs may progress to swaying, staggering,
dog-sitting, or recumbency within a few min. Horses may
be tachycardic and tachypneic during episodes, yet remain
relatively bright and alert. Episodes last for variable peri-
ods, usually 15–60 min. Several horses have died during
acute episodes (Cox, 1985). Respiratory distress, due to
paralysis of upper respiratory muscles, can occur in either
H/H or N/H animals and may require a tracheostomy.
After an episode of HYPP subsides, horses appear nor-
mal. Electromyographic examination of asymptomatic
HYPP horses reveals abnormal fibrillation potentials, com-
plex repetitive discharges with occasional myotonic poten-
337
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 dry
weight basis. Feeds high in potassium include alfalfa hay,
molasses, electrolyte supplements and kelp-based supple-
ments (Reynolds et al., 1998). Other precipitating factors
include fasting, anesthesia or heavy sedation, trailer rides
and stress (Spier, 2006). Exercise does not appear to induce
clinical signs and serum creatine kinase (CK) shows no
change 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 in
the alpha-subunit of the voltage-dependent skeletal mus-
cle sodium channel alpha-subunit (SCN4A) (Rudolph
et al., 1992). The SCN4A gene was mapped to chromo-
some 11 at 14247699–14275289 (University of California
Santa Cruz, 2008). In horses with HYPP, the resting
membrane potential is closer to firing than in normal
horses (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 a
failure 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 persistent
depolarization of muscle cells followed by temporary
weakness.
Diagnosis
Descendents of the stallion Impressive on the sire or
dam’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 present
during acute episodes, the definitive test for identifying
HYPP is the demonstration of the base-pair sequence sub-
stitution in SCN4A (Rudolph et al., 1992). 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.1 The test for HYPP
clearly 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
1
See www.vgl.ucdavis.edu.
338 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
Fig. 1. DNA test for HYPP from the Veterinary Genetics Laboratory,
University of California, Davis. The alleles are HYPP-N (normal) and
HYPP-H (affected). Each sample is amplified with two pair of primers for
an internal control of the PCR test.
to normal after the cessation of clinical signs. Some affected
horses may have normal serum-potassium concentrations
during minor episodes of muscle fasciculations (Naylor,
1994b).
Treatment
Light exercise when clinical signs are first observed can
sometimes abort an episode in mild cases. Feeding grain
or corn syrup to stimulate insulin-mediated movement of
potassium across cell membranes may be of benefit. Other
treatment 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 episodes
of 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. An
increase in extracellular calcium concentration raises the
muscle-membrane threshold potential, which attenuates
membrane hyperexcitability. To reduce serum potassium,
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. With severe
dyspnea due to laryngeal or pharyngeal obstruction, a tra-
cheostomy may be necessary.
Control
Decreasing dietary potassium and increasing renal losses
of potassium are the primary steps taken to prevent HYPP
episodes. Regular exercise and frequent turnout are benefi-
cial. Horses with HYPP can graze pastures because the
high water content of the pasture grass makes it unlikely
that horses will consume large amounts of potassium in a
short time. Ideally, horses with recurrent episodes of HYPP
should be fed a balanced diet containing between 0.6% and
1.1–1.5% total potassium concentration and meals contain-
ing <33 g of potassium (Reynolds et al., 1998). For horses
with recurrent episodes of muscle fasiculations even after
dietary alterations are instituted, acetazolamide (2–3 mg/
kg every 8–12 h PO) or hydrochlorothiazide (0.5–1 mg/kg
every 12 h PO) may be helpful. These agents exert their
effects through different mechanisms, although both induce
an increase in renal potassium ATPase activity (Cox, 1985).
In addition, acetazolamide stabilises blood glucose and
potassium by stimulating insulin secretion. Breed registries
and other associations have restrictions on the use of these
drugs during competitions.
Prognosis
In most cases, HYPP is manageable disorder, although
recurrent bouts may occur and severe episodes can be fatal.
Owners of affected horses should be strongly discouraged
from breeding these animals. Since HYPP is a dominant
trait, 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, while breeding a homozy-
gous affected horse (H/H) to a normal horse (N/N) results
in a 100% chance of producing a heterozygous affected
horse (N/H). All affected horses share the same mutation,
regardless of whether or not owners have witnessed clinical
signs in their horses (Zhou et al., 1994). Owners of affected
horses should advise veterinarians of HYPP status before
anesthesia or procedures requiring heavy sedation. Horses
descended 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. Affected
foals 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 the
United States was estimated at 8.4% and, based upon this
frequency, 0.18% of Arabian foals would be expected to be
homozygous for the gene (Bernoco and Bailey, 1998).
Clinical signs
Affected foals are clinically normal at birth as passive
transfer confers protective immunity, but foals are then
more susceptible to infectious disease and normally suc-
cumb by 5 months of age. The age of onset of infection
depends on the adequacy of passive transfer and the envi-
ronmental challenge, but usually occurs by 6–10 weeks
post-partum. Diseases of the respiratory tract are common,
caused most frequently by adenovirus or Pneumocystis
 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
carinii (McGuire et al., 1974; Perryman et al., 1978; Studd-
ert, 1978), frequently accompanied by secondary bacterial
infection (McGuire and Poppie, 1973; Perryman et al.,
1978; Studdert, 1978). Intermittent diarrhea may also be
observed (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 resulting
in a frameshift mutation and a 967 amino acid deletion
from the C terminus, including the entire PI3 kinase
domain, 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 (Bailey
et al., 1997).
During early lymphoid differentiation, distinct gene seg-
ments called variable (V), diversity (D) and joining (J),
combine to form coding sequences of immunoglobulin
and T-cell antigen receptor variable regions. This V(D)J
recombination is necessary for differential expression of
antigen receptors on B and T lymphocytes. Foals with
SCID have a 967 amino acid deletion in the enzyme
DNA-dependent protein kinase, which is required for
V(D)J recombination and for repair in the double-stranded
DNA 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 T
lymphocytes and therefore lack an endogenous humoral
or cell-mediated response.
Diagnosis
Prior to the discovery of the genetic mutation, diagnosis
of SCID was based on absolute lymphopenia (<1000/lL),
lymphoid hypoplasia on lymph node histopathology, the
absence of immunoglobulin M (IgM) in the pre-suckle
serum 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 the
DNA-PKcs gene deletion in hair or blood samples through
vetGen (www.vetgen.com).
Treatment
Supportive care may prolong the course of disease, but
affected foals eventually die by 5 months. For research pur-
poses, foals with SCID have been treated with twice weekly
IV administration of plasma hyperimmunised with anti-
adenovirus antibody and these foals have lived up to 11
339
months of age (Perryman et al., 1978). In most cases, bone
marrow transplantation and thymus transplantation have
been unsuccessful, with no evidence of immunoglobulin
production at the time of death (Ardans et al., 1977). How-
ever, immunologic reconstitution was completed in one
SCID foal that was transplanted with 1.8  108 viable bone
marrow cells/kg bodyweight (BW) that had been obtained
from a histocompatible full sibling donor (Perryman et al.,
1987). This foal was monitored for 650 days and immuno-
logic reconstitution remained complete. Treatment is not
recommended 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 affecting
foals of American Paint Horse, Quarter Horse and, rarely,
Thoroughbred breeds. The disorder has also been referred
to as aganglionic megacolon (McCabe et al., 1990) and is
the equine variant of Hirschsprung disease, a disorder
affecting humans (Metallinos et al., 1998; Yang et al.,
1998). 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.
Some affected foals may have flecks of black hair in the
main, tail or a small black body spot.
A very high incidence (>94%) of OLWS heterozygotes is
found in frame overo (Fig. 2), highly white calico overo
and frame blend overo (Santschi et al., 2001). White
coat-colored patterns with a low incidence of OLWS het-
erozygotes (<21%) include tobiano (Fig. 3), sabino, mini-
mally blend overo, and breeding-stock solid (Santschi
et al., 2001). It is important to note, however, that the
Fig. 2. A frame overo Paint Horse.
340 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
Fig. 3. A tobiano Paint Horse.
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., 1998).
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., 1983). The colic is not responsive to analgesics and
progressive abdominal distension will be seen with no fecal
material passed. The intestinal abnormalities are due to the
complete absence of intrinsic myenteric plexus in the termi-
nal small intestine, cecum and entire colon, with the ileum
most severely affected (Hultgren, 1982; Vonderfecht et al.,
1983).
Embryologically, both melanocytes and myenteric gan-
glia cells are of neural crest origin and their failure to
migrate 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 blue
eyes in addition to the pigment defects and aganglionosis
(Vonderfecht et al., 1983; McCabe et al., 1990). Foals that
have all white coat color patterns do not inexorably have
OLWS. Dominant white color patterns, albinos and some
foals heterozygous for OLWS may have all white coats
without aganglionosis.
Etiology
The genetic defect responsible for OLWS is a single
base-pair change (missense mutation) resulting in a isoleu-
cine/lysine substitution at codon 118 of the endothelin
receptor B (EDNRB) gene located on chromosome 17 at
49432374–49454137 (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 of
a seven transmembrane domain G-protein coupled recep-
tor for the endothelins. 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., 1994; Hosoda et al., 1994).
Diagnosis
A white foal with signs of colic that does not pass any
meconium is almost pathognomonic for the disease,
although radiographs, contrast studies and an ultrasound
examination may be indicated to diagnose complete bowel
obstruction. White Paint foals without evidence of colic
may not be homozygous for the OLWS mutation and
should be genetically tested. The genetic test is also useful
to determine carrier status, especially for non-frame over-
os, tobianos, and out-cropped Quarter Horses (horses with
white color markings). Testing is available through the Vet-
erinary Genetics Laboratory at the University of California
at Davis.2
Treatment and prognosis
There is no treatment available and the prognosis is
invariably 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 epitheliogenesis
imperfecta or hereditary junctional mechanobullous dis-
ease. A mutation causing JEB has been identified in Bel-
gian horses. In North America, 17% of Belgian horses
were carriers of the mutation and in Europe, 8–27% of
horses 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 was
not identified in a screening of 107 American Saddlebreds.
Clinical signs
Foals are typically born alive, but irregular, reddened
erosions and ulcerations develop in the skin and mouth
over pressure points or after mild trauma (Shapiro and
McEwen, 1995). Since the skin is so fragile, intact bullae
are rarely seen and blisters are commonly noted (Knotten-
belt et al., 2004). Extensive erosions may be present at
mucocutaneous junctions of the mouth, rectum and vulva,
and along the coronary bands. Granulation tissue along
2
See www.vgl.ucdavis.edu.
 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
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 are
also described (Shapiro and McEwen, 1995). The foal may
have temporary incisor teeth visible at birth that are white
with irregular serrated edges and pitted enamel (Baird
et al., 2003). Secondary bacterial infections, scarring,
impaired alimentation due to oral lesions and death usually
follow (Johnson et al., 1988).
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, which encodes the laminin c2 subunit chain (Spirito
et al., 2002). The Lamc2 gene is located on chromosome
5 at 108228152–108279653 (University of California Santa
Cruz, 2008). 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., 2002). Laminin 5 is widely distributed in the
basement membrane of epithelial tissues. The absence of
laminin 5 results in a cleft between the basement membrane
zone of the dermal-epidermal junction, which is evident on
microscopic evaluation of skin biopsies from affected foals
(Johnson et al., 1988). The mutation for JEB in American
Saddlebreds has not been identified but is suspected to
involve the LAM a3 gene (Lieto, 2001) located on chromo-
some 8 (Milenkovic et al., 2002). In Saddlebreds the clinical
presentation has been compared to epitheliogenesis imper-
fecta (Lieto et al., 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 (John-
son et al., 1988). Definitive diagnosis in draft horses
requires DNA testing for JEB.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.
Glycogen branching enzyme deficiency (GBED)
Glycogen branching enzyme deficiency (GBED) is an
autosomal recessive disease affecting Quarter Horse and
Pain Horse breeds. Carrier frequency estimates of 7.1%
3 5
See www.vgl.ucdavis.edu.
341
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 (Render
et al., 1999; Valberg et al., 2001; Wagner et al., 2006). If the
foal survives to term, it may appear weak and hypothermic
at 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). Affected
foals may have flexural limb deformities. 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, 2006).
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., 2004).
The GBE1 gene was mapped to equine chromosome 26
at 33459264–33657117 (University of California Santa
Cruz, 2008). Glycogen is a required energy source in the
rapidly growing fetus and neonate and is synthesized by
glycogen synthase, which creates straight chains of glucose
with alpha 1,4-glycosidic linkages and by glycogen branch-
ing enzyme, which creates a branched structure through
alpha 1,6-linkages. Tissues from GBED foals have no mea-
surable GBE-enzyme activity or immuno-detectable GBE
and cannot form normally branched glycogen (Valberg
et al., 2001). As a result, cardiac and skeletal muscle, liver
and the brain cannot store or mobilise glycogen to main-
tain normal glucose homeostasis.
Diagnosis
Common hematologic findings include a leucopenia and
moderate elevations in serum creatine kinase, aspartate
transaminase and gamma glutamyl transferase (Valberg
et al., 2001). Skeletal muscle, Purkinje cells or cardiac myo-
cytes may contain basophilic globules and eosinophilic
crystalline 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 diagnosis
as they clearly show PAS positive globular inclusions with
decreased normal background staining for glycogen in car-
diac and skeletal muscle (Valberg et al., 2001) (Fig. 4).
Definitive diagnosis requires identification of the mutation
in GBE1 by the University of California Veterinary Genet-
ics Laboratory4 or Vet Gen,5 which are both licensed by
the University of Minnesota to perform the test. Mane or
tail hairs with roots intact or fetal liver tissue can be sub-
4
See www.vgl.ucdavis.edu.
See www.vetgen.com.
342 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
Fig. 4. Semimembranosus muscle biopsy from a foal affected with GBED
stained with Periodic Acid Schiff’s stain. Note the little normal back-
ground staining for glycogen and accumulation of large globular as well as
smaller crystalline inclusions of polysaccharide.
mitted to determine if horses are affected or carriers of
GBED.
Treatment and prognosis
There is no treatment for GBED and the prognosis is
grave. It is important to test aborted foals and stillborns
for this disease or to test the dams for carrier status.
Malignant hyperthermia
Etiology
An autosomal dominant mutation has been identified in
two Quarter Horses that developed marked hyperthermia
and metabolic acidosis during inhalation anesthesia (Ale-
man et al., 2004, 2005). Both horses were homozygous
for a mutation in exon 46 of the skeletal muscle ryanodine
receptor gene (RYR1). The prevalence of the RYR1 muta-
tion in Quarter Horses is not known at this time. It is not
associated 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 the
end of anesthesia, the body temperature was 40.5 °C
(104.9 °F), while a PaCO2 of 274 mmHg and a blood pH
of 6.72 were recorded. The horse died of cardiopulmonary
arrest and profound rigor mortis was present almost imme-
diately. Hematologic changes measured 2 min after death
included 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 following
succinylcholine injection. Based on the discovery of a
genetic mutation in two Quarter Horses, a PCR based
genetic test is now available.6 It is not known whether this
mutation is present in all horses that develop malignant
hyperthermia 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 suspected
malignant hyperthermia would be pretreatment with oral
dantrolene (4 mg/kg) 30–60 min prior to anesthesia (Valv-
erde et al., 1990a; Hennig and Court, 1991). There is no
cost effective means to deliver dantrolene to horses IV once
an episode has begun. Other means to address hyperther-
mia and acidosis include external application of alcohol,
fans, chilled intravenous fluids with sodium bicarbonate
and mechanical ventilation. Unfortunately, once a fulmin-
ant episode is underway it is difficult to prevent cardiac
arrest.
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 Quarter
horse lineage. The disease has been compared to Ehlers
Danlos syndrome in humans (Hardy et al., 1988). Carrier
frequency has been recently estimated at 3.5% (Tryon
et al., 2007), with previous estimates ranging from 1.8%
to 6.5% (Tryon et al., 2005). Males and females are affected
equally (White et al., 2004). The prevalence of HERDA is
higher in cutting horses and cow horses.
Clinical signs
Clinical signs of HERDA do not typically appear until
horses are, on average, 1.5 years of age and is frequently
associated with initial saddling or trauma (Rashmir-Raven
et al., 2004; Tryon et al., 2005, 2007; White et al., 2007).
Horses affected with HERDA may present with seromas
or hematomas, open wounds or sloughing skin (Fig. 5),
6
See www.vgl.ucdavis.edu.
 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
Fig. 5. Phenotype of HERDA-affected horses. Note the extensible skin in
affected tissue that can be easily separated from underlying fascia.
loose easily tented skin that does not return to its original
position (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 in
other locations associated with trauma. Owners often
report that lesions heal slowly. There has been no evidence
of collagen-associated abnormalities in any internal organs
of affected animals at post-mortem examination (White
et al., 2004, 2007).
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., 2007). This gene likely
plays a role in the protein folding of collagens (Bachinger,
1987; Steinmann et al., 1991), however, the exact means by
which the recently discovered mutation causes disease is
unknown.
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., 2004; White
et al., 2004, 2007). Commonly observed histological
changes on skin biopsies include thinning of the dermis,
as well as thinning, fragmentation and disorientation of
collagen 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 a
large empty cleft between the upper and lower regions of
the deep dermis has been described in two HERDA cases
(Brounts et al., 2001; White et al., 2004). A genetic test
343
Fig. 6. Phenotype of HERDA-affected horses. A large hematoma
developed at approximately 1.5 years of age along the dorsum of this
affected horse.
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 and
away from other horses to prevent the development or pro-
gression of lesions (Rashmir-Raven et al., 2004). Affected
horses are often euthanased due to severity of lesions and
associated discomfort.
Polysaccharide storage myopathy (PSSM)
Polysaccharide storage myopathy (PSSM) is a glyco-
gen storage disorder affecting Quarter horses, American
Paint Horses, Appaloosas, Warmbloods and draft breeds.
The acronyms EPSM and EPSSM have also been used
for this condition. In Quarter Horse and Quarter Horse
related breeds, the mode of inheritance is autosomal
dominant (McCue et al., 2006a,b). When using the diag-
nostic criteria of amylase-resistant abnormal polysaccha-
ride on muscle biopsy samples from suspect horses, the
prevalence 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 almost
50% of muscle biopsies from Warmblood horses being
diagnosed with PSSM (McCue et al., 2006b). The true
prevalence within the various Warmblood breeds has
not been studied. PSSM is rarely identified in Arabians
and Thoroughbreds.
7
See www.vgl.ucdavis.edu.
8
See www.diagcenter.vet.cornell.edu.
344 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
Clinical signs
In Quarter Horses, the average age of onset of clinical
signs is 5 years (Firshman et al., 2003). The most common
trigger for clinical signs of PSSM is <20 min of exercise at a
walk and trot, particularly if the horse has been rested for
several days before exercise (Firshman et al., 2003). Clini-
cal signs of exertional rhabdomyolysis, including muscle
pain, 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, gait
abnormalities and muscle wasting.
In Quarter Horses with PSSM, a true clinical distinction
has not been made between homozygotes versus heterozyg-
otes; however, homozygotes generally appear more
severely affected (Valberg, personal communication). In
draft breeds, the average age at diagnosis was 8 years
(Firshman et al., 2005). It is important to note that many
draft horses with PSSM are asymptomatic. The most com-
mon clinical signs of PSSM in draft breeds include muscle
weakness, gait abnormalities, and muscle fasicultations and
exertional rhabdomyolysis which may be so severe that it
leads 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 highly
prevalent but no causal relationship was found between
these two conditions (Firshman et al., 2005). In Warmblo-
ods, the age of onset of clinical signs is between 8 and 11
years 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 the
hindquarters, failure to round the back over fences, gait
abnormalities and muscle atrophy (Quiroz-Rothe et al.,
2002; Hunt et al., 2005; McCue et al., 2006).
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 Mickel-
son, 2007). The mutation is a 10 single base-pair substitu-
tion in the glycogen synthase 1 gene located on
chromosome 10 (McCue et al., 2008). The mutation
appears to result in unregulated glycogen synthesis and
potentially impaired aerobic glycogen metabolism (Valberg
and Mickelson, 2007).
Diagnosis
Persistent elevations of serum creatine kinase and aspar-
tate transaminase (AST) may be seen in Quarter Horses
with PSSM. The median CK and AST activity of all Quar-
ter Horses with PSSM with muscle biopsies submitted to
the Neuromuscular Diagnostic Laboratory at the Univer-
sity of Minnesota was 2809 and 1792 U/L, respectively.
In draft horses and Warmbloods with PSSM, serum CK
and AST are often normal. The median serum CK and
AST activity in draft horses from which biopsies were sent
to 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/L
and 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 of
age. The characteristic features in histological sections
include the presence of subsarcolemmal vacuoles and the
presence of amylase-resistant PAS positive abnormal poly-
saccharide inclusions in the skeletal muscle fibers (Valberg
et al., 1992; Firshman et al., 2005) (Fig. 7). The eventual
accumulation of abnormal polysaccharide in skeletal mus-
cle 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.,
2002). Commercialisation of a genetic test for PSSM is
underway.
Treatment
For an acute episode, a few days of stall confinement
may be indicated in horses showing pronounced stiffness
or weakness. Hydration status should be assessed and
either oral or intravenous fluids administered if necessary
as 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-hydrated
horse to relieve anxiety and pain. It is important to note
that stall confinement should be limited to <48 h after
the episode of rhabdomyolysis as prolonged stall confine-
ment may result in an increased incidence of rhabdomyol-
ysis episodes due to PSSM.
Fig. 7. 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. Note the numerous fibers with
abnormal granular polysaccharide.
 C.J. Finno et al. / The Veterinary Journal 179 (2009) 336–347
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 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, with succes-
sive addition of 2 min intervals of walk and trot beginning
with only 4 min of exercise and working up to 30 min after
3 weeks (Valberg et al., 1997; Firshman et al., 2003; Hunt
et al., 2005). Re-evaluating serum CK is not usually helpful
in the first month, as it is often elevated, but may be used
after that time to monitor any additional muscle damage.
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.
Dietary management should be aimed at providing ade-
quate, but not excessive, calories, by decreasing the glucose
load and providing fat as an alternate energy source.
Decreasing the dietary starch to <10% of daily digestible
energy and increasing dietary fat up to 13% of daily digest-
ible energy is recommended (Ribeiro et al., 2004). Excessive
fat supplementation of 1 lb (0.45 kg) of fat per day may
lead to unnecessary weight gain and over time adverse con-
sequences 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, a feed that contains >10% of fat by weight
and <20% of starch or non-structural carbohydrates by
weight (Valberg, 2006).
Prognosis
Horses with PSSM will always have an underlying pre-
dilection for muscle soreness. It is important to institute
both dietary and exercise changes over a period of time
(1–4 months) before assessing the horse’s response. 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, respectively, and horses may return to a previous
level of performance (Firshman et al., 2003; Hunt et al.,
2005).
Conclusions
With the complete sequencing of the horse genome and
development of equine genome maps, the discovery of
equine genetic mutations will continue to expand. An
online catalogue of inherited disorders, entitled ‘Online
Mendelian Inheritance in Animals’ is available9 and pro-
vides recent information on inherited equine disorders
9
See http://omia.angis.org.au.
345
while citing relevant publications. Currently, there are
many inherited disorders for which a genetic mutation is
not yet known, including cerebellar abiotrophy, lavender
foal syndrome, Fell Pony immunodefiency, anterior seg-
ment dysgenesis, recurrent exertional rhabdomyolysis,
and hemophilia A. As the field of equine genetics continues
to develop, it is likely that many more loci for single and
polygenic 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 that
could inappropriately influence or bias the content of the
paper.
Acknowledgements
The authors would like to thank Dr. Gary Magdesian
and Dr. Stephan White for providing photographs.
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