Research in Veterinary Science 2002, 73, 231–236

doi:10.1016/S0034-5288(02)00034-6, available online at http://www.idealibrary.com on

Genetic aspects of labrador retriever myopathy

T. BLEY ,à, CL. GAILLARD , TH. BILZER§, K. G. BRAUND  , D. FAISSLERàà, F. STEFFEN§§,
S. CIZINAUSKASà, J. NEUMANN§, T. VO € GTLI   , R. EQUEYààà, A. JAGGY*,à

 
Institute of Animal Genetics, Nutrition and Housing, àDepartment for Clinical Veterinary Medicine,
Section of Neurology, University of Berne, Bremgartenstrasse 109a, CH-3012 Berne, Switzerland,
§
Heinrich-Heine-University of D€ usseldorf, Institute for Neuropathology, Moorenstrasse 5, D-40225 D€usseldorf,
Germany,   Veterinary Neurological Consulting Services, 1476 LakeviewRidge, Dadeville, AL 36853, USA,
àà
Department of Clinical Sciences, School of Veterinary Medicine, TuftsUniversity, 200 Westboro Road,
North Grafton, MA 01536, USA, §§University of Z€urich, Tierspital, Neurology Section,Winterthurerstrasse
268, CH-8057 Z€ urich, Switzerland,    Private praxis, Pfeffingerstrasse 41, CH-4053 Basel, Switzerland,
ààà
Private praxis, Birkenstrasse 35, CH-4055 Basel, Switzerland

SUMMARY

Labrador Retriever myopathy (LRM) has become a relatively common muscular disease. The objective of our pro-
spective study was to determine by segregation analyses a plausible mode of inheritance within a Labrador Retriever
population. Therefore we performed neurological examinations, as well as electromyographic and histopathological
evaluations of 58 closely related dogs. Seven dogs with an average age of 27.8 months had clinical signs consistent with
LRM including exercise intolerance or fatigue. The diagnosis was based on neurological deficits and confirmed by
histopathological results of muscle biopsy. We found in all cases obvious differences in fiber calibre size associated with
texture disturbances. In addition, we found 41 clinically normal dogs with histological findings consistent with LRM.
Three genetic models, the major gene, the mixed inheritance as well as the environmental model, were evaluated by
segregation analyses. They were applied to an extended pedigree including 164 non-randomly ascertained related
Labradors. According to phenotype the clinically examined dogs were divided into two different data sets. One data set
distinguished between clinically normal and abnormal dogs, the second data set between histopathologically normal and
abnormal dogs. We concluded that the clinical form of LRM is transmitted by a major gene and controlled by an
autosomal recessive mode of inheritance. Furthermore, for expression of the subclinical form an additional gene or an
environmental factor is responsible. Our findings suggest that LRM is similar to limb-girdle muscular dystrophy in man
and therefore, may be used in the future as an animal model. Ó 2002 Elsevier Science Ltd. All rights reserved.

LABRADOR Retriever myopathy (LRM) is a re-
latively common muscular disease that mostly affects
several dogs from the same litter (McKerrell and
Braund 1987). The disorder was first published in 1976
by Kramer and co-authors and is also known as ‘‘he-
reditary myopathy’’, ‘‘inherited myopathy’’ or ‘‘mus-
cular dystrophy’’ worldwide (McKerrell and Braund
1986; Gortel et al 1996; Klopp and Smith 2000).
The clinical signs are variable, but usually charac-
terised by generalised intermittent weakness and
ataxia. Affected dogs between 6 weeks and 7 months of
age have a short stilted gait, and sometimes demon-
strate ‘‘bunny hopping’’ and in rare cases ventroflexion
of the neck accompanied by a kyphotic posture. Pos-
tural reactions are normal or reduced and tendon re-
flexes may be absent (Amann 1987). The musculature
shows generalised atrophy but is not painful on pal-
pation. In addition, serum levels of creatine kinase
(CK) activity may be moderately increased (Gortel
*
Corresponding author: A. Jaggy, Birkenstrasse 35, CH-4055 Basel,
Switzerland.
E-mail: tim_bley@hotmail.com
et al 1996). Severely affected Labradors may have a
megaoesophagus that is confirmed radiographically
(Watson et al 1988). In most affected dogs electromy-
ography (EMG) reveals positive sharp waves, fibrilla-
tion potentials and bizarre high frequencies, however,
motor nerve conduction velocities (MNCV) are within
normal limits (Moore et al 1987).
The histopathological evaluation of muscle biopsies
confirms the diagnosis of LRM. The characteristic
findings are the reduction in number, necrosis and fiber
group atrophy of type 2 fibers. Other morphological
changes are fiber regeneration, proliferation of con-
nective tissue, internal nuclei and sometimes phagocy-
tosis. In some specimens muscle fibers are
hypertrophic. Peripheral nerves do not show histo-
pathological changes (McKerrell and Braund 1986).
The pathogenesis of LRM is still unclear and limited
studies of hemodynamic and metabolic aspects of af-
fected muscles have been inconclusive (Amann et al
1988; Mehta et al 1989; Olby et al 2001).
To date, investigations of the genetic aspects of
LRM have included only small groups of sporadically
affected dogs. It has been postulated that the disease is
transmitted by a simple autosomal recessive mode of

0034-5288/02/$ - see front matter Ó 2002 Elsevier Science Ltd. All rights reserved.
232
inheritance (Kramer et al 1981; McKerrell and Braund
1987). Since Labrador Retriever myopathy affects both
sexes, the disease is well distinguishable from the X-
linked muscular dystrophies of the Groenendaeler
Shepherd, the Samoyed or the Golden Retriever (Van
Ham et al 1993; Valentine et al 1986).
We had the opportunity to perform a neurological
examination, as well as electromyographic and histo-
pathological evaluation on 58 closely related Labrador
Retrievers. The purpose of our prospective study was
to characterise the disease within that population and
to establish a plausible mode of inheritance by segre-
gation analyses.
MATERIALS AND METHODS
Dogs and clinical evaluations
The first case presented at the Clinic for Small An-
imals in Berne, Switzerland, was a 4-month-old male
Labrador Retriever (dog #843, Fig 1). Thereafter, his
whole nuclear family (8 littermates and parents), two
fullsib families (n ¼ 16) and 31 further related dogs
were evaluated. Thus 58 Labradors were included in
our investigation, of which 33 were male and 25 female
FIG 1: Extended pedigree including 164 dogs. / , female/male, not examinated; / , female/male; / , female/male, biopsy abnormal; / , female/male,
clinic and biopsy abnormal. Dog #843 was the first case of histologically confirmed myopathy. Every dog is marked by an identification number.
T. Bley et al
with an average age of 39.9 months (range: 4–96
months).
Physical and neurological examinations were carried
out on all Labradors. In addition, serum CK levels were
determined in 19 dogs. For further diagnostic proce-
dures, probands were anesthetised with 3–7 mg/kg
bodyweight PropofolÒ given intravenously, and there-
after incubated and maintained with halothane.
Thirty-two Labradors were tested by EMG as described
by Moore et al (1987). Briefly, we used a monopolar
exploring electrode and a ground electrode (Medelec
Accessories, Oxford Instruments, Hawthorne, USA).
The following muscles were examined for the thoracic
limbs: m. extensor carpi ulnaris, m. flexor digitalis su-
perficialis, m. biceps and triceps brachii; for the pelvic
limbs m. gastrocnemius, m. biceps femoris, m. flexor
digitalis lateralis and m. semitendinosus. Additionally,
we investigated paravertebral and the muscles of mas-
tication (m. masseter and m. temporalis). MNCV of
either the left or the right peroneal nerve (n ¼ 6) was
determined using Teflon-coated electrodes in combi-
nation with a ground electrode (Moore et al 1987). The
recorded potentials were displayed on the Multiliner E
Neuroscreen PLUS (Jaeger/Toennies) and stored on
computer for further evaluations.
 Genetic of Labrador Retriever myopathy
Muscle biopsies were collected from all 58 Labrador
Retrievers as described by Amann (1998). Further-
more, muscle samples from 12 healthy dogs of various
breeds, ages and sexes were collected.
The selected muscle samples [m. semitendinosus (n
¼ 38), m. tibialis cranialis (n ¼ 15), m. quadriceps
femoris (n ¼ 14), m. biceps femoris (n ¼ 2), m. triceps
brachii (n ¼ 1) and m. rectus abdominis (n ¼ 2)] were
frozen in isopentane cooled in liquid nitrogen
()135 °C) and cut in transverse planes at 5 lm with the
cryostat microtome maintained at )20 °C (Braund et al
1978). Sections were stained according to the following
histological and histochemical techniques: hematoxylin
and eosin (HE), GomoriÕs modified trichrome/Engel,
reduced nicotine-amide adenine dinucleotide–tetrazo-
lium reductase (NADH-TR), routine adenosine tri-
phosphatase at pH 9.4 (ATPase), oilred/Sudan,
succinate dehydrogenase (SDH) and periodic acid–
Schiff. Muscle biopsy specimens revealed signs of se-
vere muscle fiber degeneration, as evidenced by a
spectrum of muscle fiber diameters caused by fiber at-
rophy and compensatory hypertrophy, fiber disruption
and degradation, metachromasia of damaged muscle
fibers in the Gomori modified trichrome/Engel reaction
and loss of type 2 fibers as demonstrated by the
NADH-TR reaction. Nerve biopsies were performed
as described by Braund et al (1982). Briefly, nerve tis-
sue was stretched on wooden tongue depressors using
pins, fixed in 2.5% glutaraldehyde and processed for
paraffin fixation.
Pedigree and segregation analyses
A total of 164 Labrador Retrievers with pedigree
certificates were included in the study, of which 58 dogs
were clinically evaluated as previously described. The
latter population was analysed with two different: data
sets as follows: data set 1 included clinically and his-
topathologically normal Labradors (n ¼ 10); in addi-
tion, 48 dogs with histopathological findings were
classified as abnormal regardless of whether the clinical
results were normal (n ¼ 41) or abnormal (n ¼ 7).
Data set 2 consisted of clinically healthy dogs regard-
less of the histological results; they were classified as
being normal (n ¼ 51). However, dogs with concomi-
tant clinical signs of LRM and pathological findings
were classified as being abnormal (n ¼ 7).
Three different genetic models, that estimate allele
frequencies and transmission probabilities were tested
by segregation analyses. Calculations were performed
by the maximum likelihood procedures (Elston and
Steward 1971; Morton and McLean 1974; Lalouel et al
1983) using the statistical software PAP package
(Hasstedt 1994) and maximised with the NSPOL pro-
gram (Gill et al 1986). The differences between the
likelihoods of the following three models were com-
pared with likelihood ratio tests.
1. The major gene model: The major locus was mod-
eled having two alleles in the Hardy–Weinberg equi-
librium, i.e. three different genotypes could be
distinguished. This model, which provided estimates
233
for allele frequency p and the allele transmission
probabilities, was calculated under two different as-
sumptions: the latter mentioned were set according
to Mendelian segregation, namely 1, 1/2 and 0 re-
spectively, and the values of the general transmis-
sion probability could vary between 0 and 1.
2. The mixed inheritance model: The major locus was
modeled as in the major gene model. Furthermore,
the underlying liability was assumed to be addition-
ally controlled by a normally distributed additive
polygenic component with mean 0 and standard de-
viation ra . This model was described by the same pa-
rameters as in the major gene model and by the
polygenic heritability, where h2 ¼ r2a =r2a þ ð1  r2a Þ.
3. The environmental non-transmission model: Neither
a major gene effect nor polygenic effects were as-
sumed. It modeled the situation as if no genetic com-
ponents had any influence on the disease.
FisherÕs exact t-test was used to evaluate frequencies of
morphological changes in muscle samples between
males and females, as well as between clinically af-
fected and normal dogs (SAS 1996). The significance
level was set at P 6 0.05.
RESULTS
Dogs
Myopathy was clinically diagnosed and historically
confirmed in 7 Labrador Retrievers (#572, 843, 844, 1025,
1026, 1027, and 1028) that were presented for exercise
intolerance or fatigue (Fig 1). Their age ranged between
4 and 69 months (average: 27.8 months). The neurolog-
ical examination revealed poorly muscled dogs (n ¼ 6)
with decreased postural reactions (n ¼ 7) including ab-
normal wheelbarrowing (n ¼ 7) and hopping (n ¼ 7).
All spinal reflexes were decreased (n ¼ 3) to absent
(n ¼ 4). All results of blood (n ¼ 19) analysis including
serum C K level determination were normal with the ex-
ception of dog #843 (C K ¼ 730 U/l). Electrodiagnostic
examination was done in 32 dogs. Fibrillation potentials
and positive sharp waves in all proximal limb and par-
avertebral muscles were found in four dogs, all belonging
to the clinically abnormal group. The results of MNCV
(n ¼ 11) were within normal limits (n ¼ 7).
The histopathological changes were not uniform in all
affected dogs. They consisted of marked differences in
fiber calibre size (P < 0:001) associated with texture
disturbances (Fig 2). In most cases type 2 muscle fibers
were dystrophic (P < 0:001) (Fig 3). The latter men-
tioned condition (P < 0:021) as well as hypertrophy
(P < 0:05) was observed in type 1 fibers (Figs 3, 4). Ne-
crosis (P < 0:001) and atrophy (P < 0:05) of fiber type 1
were also significantly frequent. The mean diameter of
the smallest fibers was less than 5 lm and of the largest
fibers more than 150 lm. Replacement of muscle fibers
with fat and fibrous tissue was obvious (P < 0:001).
Mononuclear infiltrates, regeneration, hypertrophy of
type 2 fibers, pathological enzyme activity, giant cells
and phagocytosis were uncommon findings (Fig 2).
234 T. Bley et al
FIG 2: Frequency values of single histopathological findings of abnormal
muscle samples compared to normal muscles.
FIG 3: Section of tibialis cranialis muscle of a clinical healthy Labrador Re-
triever (#746). Hematoxylin and eosin staining with predominant variation in
muscle fiber calibre size as a consequence of necrosis (black arrow), atrophy
(white arrow) and hypertrophy (white arrowhead). Connective tissue (curved
white arrow) is increased.
Histopathological evaluation of all peroneal nerves was
normal (n ¼ 6).
Dogs with clinically manifest signs of myopathy had
significantly more hypertrophy of type 2 and type 1 fi-
bers than did healthy Labradors (P ¼ 0:005 and
P ¼ 0:008 respectively). The healthy group was signif-
icantly older than the affected group (57.7 months).
However, there was no significant difference in histo-
pathological findings between the sexes.
Pedigree and segregation analyses
The pedigree map revealed the genetic relation
among the 58 clinically evaluated Labrador Retrievers
FIG 4: Section of semitendinosus muscle of a clinically healthy Labrador
Retriever (#846): type 1 fibers (white arrow) coloured brown, deficient type 2
fibers (black arrow) coloured blue. NADH-TR/ATPase (pH 9.4) staining.
(Fig 1). Twenty-eight dogs were members of three
fullsib families (#741–746, 828–833 and 843–851). One
litter (#843–851) showed a high inbreeding coefficient
(F ¼ 0:11) with three common ancestors (#282, 651 and
938). The fullsib #836 and 838 had the same inbreeding
coefficient (F ¼ 0:11) with #282, 651 and 659 as com-
mon ancestors. The other dogs were only slightly in-
bred (F < 0:03) or not inbred at all.
Results of the segregation analyses are summarised
in Table 1. In data set 1 the allele frequencies of the
deleterious allele were high in all genetic models (0.71
and 0.83 respectively). The major gene model with
Mendelian segregation showed a much lower maxi-
mum likelihood than the environmental model. No
significant differences were observed among the major
gene, mixed inheritance and environmental models.
The estimated transmission probabilities of homozyg-
otes were as expected in all models, whereas those of
heterozygotes showed a deviation from the expected
values (0.11 instead of 0.5).
In data set 2 the environmental model showed the
lowest likelihood. The Mendelian segregation model
was 15 times more probable than the environmental
model, therefore Mendelian inheritance was more
likely to occur. The likelihood ratio tests, however,
did not differ between the analysed genetic models.
In addition, the frequency of the deleterious allele
was 0.31 in the Mendelian and 0.26 in the other
genetic models. The transmission probabilities of the
homozygotes were as expected, whereas the hetero-
zygotes had only slightly different results from the
expected.
DISCUSSION
The goal of our prospective study was to determine
by segregation analyses the genetic aspects of myopa-
thy in a Labrador Retriever population. Thus a large
group of closely related dogs was collected for neuro-
logical, electrodiagnostic and histopathological evalu-
ations.
The clinical manifestation of LRM was documented
in 7 animals. They mainly presented with exercise in-
 Genetic of Labrador Retriever myopathy 235

TABLE 1: Genetic parameters of segregation analyses for myopathy in Labrador Retrievers expressed through different
genetic models
Genetic parameters Major gene with Mendelian Major gene Mixed inheritance
segregation
Data set Data set Data set
1 2 1 2 1 2
Frequency of the normal allele (A) 0.17 0.69 0.29 0.74 0.29 0.74
(0.07) (0.12) (0.15) (6.16) (0.15) (0.16)
Transmission probability of AA 1a 1a 0.99 1.00 0.99 1.00
allele A in genotype (0.51) (0.00) (0.15) (0.00)
Aa 0.5a 0.5a 0.11 0.44 0.11 0.44
(0.10) (0.16) (0.10) (0.16)
aa 0a 0a 0.05 0.00 0.05 0.00
(0.05) (0.00) (0.05) (0.00)
Polygenic heritability – – – – 0.02 0.02
(0.00) (0.00)
)2 In likelihood 68.18 32.28 50.24 32.13 50.24 32.13
Data are mean (standard error); bold: estimated parameters.
The environment model has a calculated )2 In likelihood of 52.15 for data set 1 and 37.67 for data set 2.
a
Present value; –: no value calculated.

tolerance and fatigue. All dogs exhibited signs of lower
motor neuron dysfunction. It is well established that
LRM is only confirmed by histological evaluation
(McKerrell and Braund 1986). Therefore, we per-
formed a standardised muscle biopsy on every single
case. In addition, our controls included 10 related
Labrador Retrievers, as well as 12 dogs of different
breeds. Their histological results were consistently
negative. Furthermore, we examined closely related
nuclear families, as well as unrelated single Labradors.
To our surprise we found a large number of clinically
normal dogs (n ¼ 41) with histological findings consis-
tent with myopathy. However, hypertrophy of type 2
and type 1 fibers was only observed in clinically ab-
normal dogs. One explanation could be that fiber hy-
pertrophy may reflect an attempt to compensate
malfunction through loss of morphological structures
and indicate an advanced state of myopathy. We think
that these observations may represent a subclinical
form of LRM. Because our probands are used as guide
dogs and therefore are not stressed by extensive
physical exercise, we believe that the latent form may
become obvious only under strong physical work.
Abnormal EMG findings were only obvious in dogs
with clinical symptoms. All other dogs had no abnor-
malities. Thus, this diagnostic procedure was not sen-
sitive enough to detect subclinical stages of the disease.
Similar results have been documented by Hoskins and
Root (1983), who stated that histologically confirmed
LRM is not always accompanied by concurrent EMG
abnormalities such as fibrillation potentials and posi-
tive sharp waves.
We were able to show the genetic relationship
among the clinically evaluated Labradors by pedigree
analyses and prove, thereafter, that the disease has
indeed a hereditary basis. In addition, the results of
data set 1, which phenotypically distinguished between
histopathologically normal and abnormal animals, were
consistent with an autosomal recessive inheritance as
already suggested by other authors (Kramer et al 1976;
Gortel et al 1996). However, in our present families the
frequency of the deleterious allele was extremely high,
with a range from 0.31 to 0.26. Moreover, the results of
segregation analyses of data set 2, which gives a phe-
notypical distinction between clinically normal and
abnormal animals, confirmed the previous postulated
mode of inheritance. We therefore concluded that a
simple recessive Mendelian inheritance did not fit the
data, although the presence of a major gene with a very
high frequency of deleterious allele (0.71) was most
likely. Since its transmission probability was very high
(0.89 instead of 0.5), we showed that this allele does,
however, not segregate according to Mendelian ex-
pectation We do not believe that the segregation dis-
tortion is caused by a preferential selection of gametes
that include the deleterious allele. However, the results
of the segregation could also be influenced by false-
negative histopathological results. Indeed the clinically
healthy and histopathologically normal parents #47 and
824 (Fig 1) had one litter of six offspring (#741–746)
with histopathologically confirmed LRM. We con-
cluded from all these results that the clinical form of
LRM is localised on a single major gene and trans-
mitted by an autosomal recessive mode of inheritance,
whereas the subclinical form may be expressed by an
additional gene. We cannot exclude, however, that the
latter may be influenced by some environmental
factors.
In regard to these bivalent results, we postulate that
several forms of a hereditary myopathy may be present
in our dog population. It is interesting to note that the
limb-girdle muscular dystrophy (LGMD) of man re-
presents a heterogeneous group of diseases that is
characterised by mild to severe forms of progressive
muscle degeneration (Moreira et al 1997). In addition,
the clinical and histopathological findings are similar to
the described findings in our dogs (Fardeau et al 1996).
Hence, LRM could be an acceptable animal model for
further research purposes.
Additional genetic investigations will have to study
an extensive group of phenotypically characterised
Labrador Retrievers. They could lead to further ge-
netic results and finally to the development of genetic
markers. The collaboration of breeders for routine
muscle screening and appropriate strategies are needed
to selectively control the disease.
236 T. Bley et al
ACKNOWLEDGMENTS
This research was supported by the Albert-Heim-
orderung Ky-
Stiftung and by the ‘‘Gesellschaft zur F€
nologischer Forschung e.V. (GKF)’’. We thank Dr C.
Rohrer Bley for carefully reading the manuscript.
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