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Canine epilepsy: A genetic counselling programme for Keeshonds

Authors:

Abstract

The predisposition of keeshonds (Dutch barge dogs) to an idiopathic epilepsy appears to be determined by a single autosomal recessive gene. The pedigrees of 15 litters which included animals diagnosed as epileptic ('fitters') were compared with those of 34 contemporary, normal animals. The pedigrees of all the fitters traced back, on both the paternal and maternal sides, to a common ancestor. Subsequently, further pedigrees and details of litters were gathered. If both parents of a fitter were heterozygous ('carriers'), the progeny (120 in number) of all known carrier x carrier matings would be expected to have a ratio of three phenotypically normal animals to one fitter, that is, 90:30. The ratio observed (91:29) was not significantly different. The Keeshond Club has published a list from which the identities of carriers can be inferred, with the intention that known carriers should be excluded from breeding. A genetic counselling programme has been in operation since 1989, which is based on advising breeders on the probability that the offspring of proposed matings would be fitters or carriers; advice has been given on 77 proposed matings. The mean probability that the proposed matings would result in carriers has declined significantly, and this is consistent with a decline in the frequency of the gene for this form of epilepsy in the breed.
The
Veterinary
Record,
April
13,
1996
Canine
epilepsy:
a
genetic
counselling
programme
for
keeshonds
S.
J.
G.
Hall,
M.
E.
Wallace
Veterinary
Record
(1996)
138,
358-360
The
predisposition
of
keeshonds
(Dutch
barge
dogs)
to
an
idiopathic
epilepsy
appears
to
be
determined
by
a
single
auto-
somal
recessive
gene.
The
pedigrees
of
15
litters
which
includ-
ed
animals
diagnosed
as
epileptic
('fitters')
were
compared
with
those
of
34
contemporary,
normal
animals.
The
pedigrees
of
all
the
fitters
traced
back,
on
both
the
paternal
and
mater-
nal
sides,
to
a
common
ancestor.
Subsequently,
further
pedi-
grees
and
details
of
litters
were
gathered.
If
both
parents
of
a
fitter
were
heterozygous
('carriers'),
the
progeny
(120
in
num-
ber)
of
all
known
carrier
x
carrier
matings
would
be
expected
to
have
a
ratio
of
three
phenotypically
normal
animals
to
one
fitter,
that
is,
90:30.
The
ratio
observed
(91:29)
was
not
signifi-
cantly
different.
The
Keeshond
Club
has
published
a
list
from
which
the
identities
of
carriers
can
be
inferred,
with
the
inten-
tion
that
known
carriers
should
be
excluded
from
breeding.
A
genetic
counselling
programme
has
been
in
operation
since
1989,
which
is
based
on
advising
breeders
on
the
probability
that
the
offspring
of
proposed
matings
would
be
fitters
or
car-
riers;
advice
has
been
given
on
77
proposed
matings.
The
mean
probability that
the
proposed
matings
would
result
in
carriers
has
declined
significantly,
and
this
is
consistent
with
a
decline
in
the
frequency
of
the
gene
for
this
form
of
epilepsy
in
the breed.
GENETIC
diseases
are
widespread
in
dogs
(Nicholas
1987,
Patterson
and
others
1989).
In
1964
the
idea
was
first
published
(Croft
and
Stockman
1964)
that
there
was
a
genetic
tendency
to
epilepsy
('fitting')
in
the
keeshond
breed
and
keeshonds
born
between
1956
and
1972
were
tested
by
electroenceph-
alography
(EEG);
however,
the
EEG
patterns
were
found
not
to
be
related
to
fitting
and
no
genetic
explanation
was
found
for
the
EEG
observations
(Wallace
1975).
However,
there
seemed
to
be
a
familial
tendency
towards
fitting
in
the
keeshond,
as
in
other
breeds,
(Cunningham
and
Farnbach
1988)
so
further
study
was
warranted.
With
only
87
registrations
at
the
Kennel
Club
in
1993
and
42
breeders
in
the
current
Keeshond
Club
handbook,
this
is
one
of
the
rarest
canine
breeds
in
Britain
(total
registrations
of
all
breeds
in
1993:
235,893).
The
breed
originated
in
the
Netherlands
(Gatacre
1938)
but
is
now
best
established
in
Britain,
Sweden
and
the
USA.
Apart
from
idiopathic
epilepsy
the
only
defects
which
have
been
described
as
genetic
in
the
breed
are
a
cardiac
condition
(Patterson
and
others
1993)
and
an
insulin-dependent
diabetes
mellitus
(Kramer
and
others
1988).
Canine
epilepsy
has
not
been
extensively
documented
and
from
the
perspective
of
human
medicine
the
dog
is
not
listed
as
one
of
the
species
that
can
pro-
vide
an
animal
model
(Buchhalter
1993).
This
paper
presents
a
genetic
model
for
epilepsy
in
the
keeshond
in
Britain
and
reports
on
the
progress
of
a
counselling
scheme
which
is
operated
through
the
Keeshond
Club.
Materials
and
methods
Genetic
investigations
As
a
first
step,
the
pedigrees
of
the
litters
born
between
1978
and
1985
which
included
animals
diagnosed
by
veterinary
sur-
geons
as
epileptic
(15
pedigrees),
together
with
34
pedigrees
of
litters
which
did
not
show
the
condition,
were
examined.
The
pedigree
details
were
entered
into
the
IBM
3081
computer
of
Cambridge
University
and
the
program
of
Falco
(1975)
was
used
to
calculate
inbreedings
and
identify
common
ancestors
(those
animals
which
are
found
on
both
paternal
and
maternal
sides
of
the
pedigree).
The
simplest
hypothesis,
that
the
condition
was
due
to
or
closely
linked
with
a
single
autosomal
gene,
was
tested
by
assuming
that
both
parents
of
an
epileptic
pup
were
themselves
carriers,
heterozygous
for
the
normal
and
the
'fitter'
gene.
Further
pedigrees
and
litter
details
were
examined
to
give
a
total
of
26
lit-
ters
of
which
both
parents
were
carriers,
and
for
which
the
num-
bers
of
normal
and
affected
progeny
were
known.
The
progeny
ratio
was
compared
with
the
Mendelian
phenotypic
ratio
(3:1)
expected
for
such
matings.
Of
these
litters,
five
included
no
epileptic
pups.
To
take
account
of
possible
bias
in
this
sample,
a
segregation
analysis
was
applied
to
the
remaining
21
litters,
using
the
modified
singles
method
described
by
Nicholas
(1987).
Genetic
counselling
scheme
The
probabilities
that
the
progeny
of
known
carriers
were
them-
selves
carriers,
and
that
matings
between
animals
would
give
rise
to
carriers
or
fitters,
were
calculated
by
methods
similar
to
those
described
by
Grant
(1976).
A
mating
between
a
carrier
and
a
nor-
mal
animal
has
a
0
5
(50
per
cent)
probability
of
producing
a
car-
rier,
but
zero
probability
of
producing
a
fitter.
A
mating
between
two
carriers
has
probabilities
as
follows:
normal
0.25,
carrier
0-5,
fitter
0-25.
It
was
presumed
that
the
fitter
condition
is
effectively
lethal
before
mating
(because
fitters
were
not
knowingly
used
for
breeding),
so
the
probability
of
the
progeny
of
the
two
carriers
being
a
carrier
at
the
time
of
mating
was
taken
as
0-50/0-75,
that
is,
0-667.
If
this
animal
is
mated
with
one
of
carrier
probability
x,
the
probability
that
the
mating
is
a
carrier
x
carrier
mating
(a)
is
x(0.667),
the
probability
that
it
is
a
normal
x
normal
mating
(b)
is
(I-x)
(1-0-667)
and
the
probability
that
it
is
a
normal
x
carrier
mating
(c)
is
(l-x)
(0-667)
+
(x)
(1-0-667).
Epileptic
pups
can
result
only
from
mating
a
and
would
be
on
average
one
in
four
of
the
progeny,
that
is,
the
probability
of
a
given
pup
being
epileptic
is
x(0-667)/4.
Carrier
pups
can
result
from
mating
a
(one
in
two
of
the
offspring)
and
from
mating
c
(one
in
two
of
the
offspring);
the
probability
of
a
given
pup
being
a
carrier
is
therefore:
[x(0-667)/2]
+
((I-x)
(0-667)
+
(x)(1-0-667)}/2
The
keeshond
epilepsy
counselling
scheme
has
operated
as
fol-
lows.
Since
October
1989
members
of
the
Keeshond
Club
have
sent
the
pedigrees
of
their
breeding
animals
to
a
nominated
committee
member
who
forwards
them
to
one
of
the
authors
(S.
J.
G.
H.).
Members
who
have
sent
pedigrees
are
allowed
to
receive
advice
on
proposed
matings.
The
probabilities
of
a
mating
producing
fitters
and
carriers,
and
the
inbreeding
coefficient
of
the
progeny
of
such
a
mating,
are
calculated
and
the
breeder
is
advised
whether
or
not
to
proceed.
To
review
progress,
matings
were
tabulated
according
to
year,
the
identities
of
the
proposed
sire
and
dam,
and
the
inbreeding
coefficients
and
carrier
probabilities
of
the
sire,
dam
and
progeny,
and
the
probability
of
fitters
in
the
progeny.
The
data
were
S.
J.
G.
Hall,
MA,PhD,
Department
of
Clinical
Veterinary
Medicine,
Madingley
Road,
Cambridge
CB3
OES
M.
E.
Wallace,
MA,
PhD,
Department
of
Genetics,
Downing
Street,
Cambridge
CB2
3EH
Dr
Wallace's
present
address
is
Town
End,
Duck
End,
Girton
CB3
OPZ
358
group.bmj.com on July 15, 2011 - Published by veterinaryrecord.bmj.comDownloaded from
The
Veterinary
Record,
April
13,
1996
A
A
C
A
A
A
A
25
between
1980 and
1989,
and
five
between
1990
and
1994.
The
age
of
onset
ranged
from
eight
months
to
six
years
(mean
30
5
months,
median
24
months).
On
the
presumption
that
both
parents
of
a
fitter
are
carriers,
52
carriers
(22
males
and
30
females)
have
been
identified.
Operation of
the
genetic
counselling
scheme
A
Fifty-nine
breeders
have
notified
a
total
of
164
pedigrees
to
the
scheme,
and
since
October
1989
advice
has
been
provided
on
77
matings
proposed
by
27
different
breeders.
On
each
occasion,
the
5+A
A
B
A
B
breeder
has
sought
advice
on
the
suitability
of
one
or
more
dogs
A
AB
B B
for
mating
with
a
particular
bitch.
The
calculated
probabilities
of
A
A
producing
fitters
range
from
0-003
to
0
129,
and
the
probabilities
0~
zA
A
of
producing
carriers
range
from
0
161
to
0
5.
The
distribution
is
A
A
A
as
follows:
carrier
probability
<0
20,
nine;
0.20
to
0
249,
21;
0
25
B
to
0
299,
17;
0
30
to
0
349,
17;
and
>035,
13.
The
probabilities
A
B
A
calculated
for
the
proposed
matings
have
declined
since
the
incep-
A
5+
B B
tion
of
the
scheme
(Fig
1).
Twenty
of
the
proposed
matings
have
A
been
advised
against.
The
mean
inbreeding
of
the
prospective
~~A
A
A
B
A
keeshond
sires
is
5-9
per
cent,
of
the
dams
6-4
per
cent
and
of
the
A
c
litters
that
would
result,
6-4
per
cent.
A
The
164
keeshonds
that
have
been
notified
to
the
scheme
are
by
A
A
78
sires
out
of
144
dams.
Only
10
sires
and
15
dams
had
carrier
|
A
A
probabilities
of
0.
The
median
carrier
probabilities
of
the
animals
(followed
by
the
mean
[sem]
in
brackets)
were
for
the
78
sires
5+
0
312,
(0.461
[0.0282]);
for
the
144
dams
0
357
(0.394
[0.0216])
and
for
the
164
litters
that
would
result
0
348
(0.387
[0.0162]).
A
matched-pairs
t
test
showed
that
the
carrier
probabilities
of
the
Year
sires
significantly
greater
than
those
of
the
dams
(P<0.05).
FIG
1:
Plot
of
probabilities
that
the
progeny
of
proposed
matings
would
be
carriers,
according
to
the
year
in
which
the
mating
was
proposed.
The
regression
analysis
of
variance
is
significant
and
the
Pearson
correlation
coefficient
is
0-39
(sum
of
squares
due
to
regres-
sion
0-0818,
residual
0-4418,
degrees
of
freedom
1,72,
F
13-933,
P<0
0005).
The
equation
of
the
fitted
straight
line
is
y=2-538-0-0243x.
A
signifies
one
observation,
B
two
and
C
three
analysed
statistically
by
the
SAS
package
(Helwig
and
Council
1979).
The
extent
to
which
the
probabilities
of
carriers
and
fitters
being
produced
by
the
proposed
matings
has
changed
from
1989
to
the
end
of
1994
was
investigated
by
regression
analysis.
Results
Genetic
basis
for
the
conditioni
Twenty-six
matings
of
carriers
produced
91
normal
and
29
fit-
ter
offspring;
this
ratio
was
not
significantly
different
from
the
3:1
ratio
predicted
on
the
basis
of
the
genetic
hypothesis.
When
only
the
21
matings
which
produced
at
least
one
fitter
were
considered
a
segregation
frequency
of
0
1625
with
variance
2-36
x
10-3
was
deduced,
which
is
not
significantly
different
(X2
=
3
246,
X2
for
P
005
=
3-841)
from
the
segregation
frequency
of
0-25,
equiva-
lent
to
the
3:1
phenotypic
ratio.
All
the
fitters
in
this
study
were
found
to
be
inbred
to
one
of
two
common
ancestors,
either
a
dog
born
in
1971
and
widely
used
for
breeding,
or
his
great
grandsire,
that
is,
the
pedigree
of
each
fitter
featured
one
of
these
animals
on
both
the
paternal
and
the
maternal
sides.
The
mean
(sem)
inbreeding
coefficient
of
the
15
litters
includ-
ing
fitters
which
were
initially
studied
was
0
076
(0.013)
and
not
significantly
greater
than
that
of
the
34
normal
litters
(0.
113,
[0.011]).
Incidence
of
idiopathic
epilepsy
In
total
39
fitters
have been
reported
(20
males
and
19
females)
from 34
litters,
of
which
four
were
born
between
1970
and
1979,
Discussion
For
genetic
defects
in
dogs
to
be
inherited
as
a
single
autosomal
recessive
is
not
unusual
(Patterson
and
others
1989)
but
the
authors
believe
that
this
is
the
first
evidence
that
a
predisposition
to
canine
epilepsy
can
be
inherited
in this
way.
In
human
epilep-
sies,
this
mode
of
inheritance
has
been
suggested,
as
has
autoso-
mal
dominant
inheritance
for
some
conditions
associated
with
epilepsies
(Bird
1987,
1994).
The
strongest
evidence
for
the
model
proposed
is
the
phenotyp-
ic
ratio
of
3:1
of
the
progeny
obtained
from
pairs
of
animals
which
were
both
believed,
because
of
their
being
parents
of
fitters,
to
be
carriers.
To
guard
against
a
possible
bias
in
these
progeny,
a
conservative
segregation
analysis
was
applied,
which
gave
a
result
that
is
consistent
with
this
evidence.
That
all
the
fitters
were
inbred
to
a
single
dog
or
his
great
grandsire
is
consistent
with
the
model
and
provides
a
mechanism
by
which
the
gene
was
distribut-
ed
throughout
the
breed.
It
might
have
been
expected
that
the
fit-
ters
would
have
been
more
inbred
than
the
normal
dogs,
but
this
is
not
a
definitive
test
of
the
model;
in
general
it
appears
that
the
keeshond
despite
its
small
population
is
not
a
particularly
inbred
breed,
being
similar
in
this
respect
to
samples
of
boxers
(mean
inbreeding
0.042),
German
shepherd
dogs
(0.098)
and
greyhounds
(0
057)
(Willis
1989).
The
gene
which
it
is
suggested
predisposes
keeshonds
to
idiopathic
epilepsy
is
probably
widespread
within
the
breed.
With
25
fitters
being
born
between
1980
and
1989,
during
which
period
2009
keeshonds
were
registered,
on
the
presumption
of
Hardy-
Weinberg
equilibrium,
the
mean
gene
frequency
over
this
period
would
have been
0
1
12
with
398
carriers
registered.
However,
since
that
time
two
policies
have
been
put
into
effect,
first,
to
publish
a
list
from
which
the
identities
of
known
carriers
can
be
inferred
with
a
view
to
avoiding breeding
from
them
and,
secondly,
to
import
breeding
stock
from
populations
believed
to
be
free
of
the
condition.
Although
it
is
possible
that
fitters
have
either
not
been
reported,
or
have
yet
to
show
the
condition,
the
decrease
in
the
notifications
of
fitters
since
1989
suggests
that
these
policies
have been
effective.
It
is
possible,
too,
that
the
genetic
counselling
scheme
has
also
played
a
part.
What-
ever
the
cause
or
causes,
it
is
evident
that
the
prospective
sires
and
A
5+
.I
a)
.=
E
0
o
0
0.e
.0
E
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group.bmj.com on July 15, 2011 - Published by veterinaryrecord.bmj.comDownloaded from
The
Veterinary
Record,
April
13,
1996
dams
being
submitted
for
assessment
are
less
likely
to
be
carriers
than
were
the
sires
and
dams
submitted
at
the
beginning
of
the
scheme
(Fig
1).
With
time,
the
criteria
for
advising
for
or
against
matings
will
need
to
be
changed.
At
present,
proposed
matings
which
would
give
pups
with
a
carrier
probability
of
26
per
cent
or
over
are
gen-
erally
advised
against,
and
if
a
mating
would
be
very
inbred
(taken
as
over
0.12)
this
disadvantage
would
also
be
brought
to
the
breeder's
attention.
These
figures
are
not
deduced
a
priori,
but
are
set
so
as
not
to
reject
too
many
matings.
They
will
not
neces-
sarily
be
appropriate
for
other
breeds.
It
is
also
clear
that
the
pre-
sent
study
would
benefit
from
the
application
of
modem
tech-
niques
of
molecular
genetics
(Spurling
and
others
1983,
Bonner
1994)
and
if
this
could
be
done
the
precision
of
the
advice
offered
would
be
greatly
improved.
Acknowledgements.
-
Mrs
Gina
Weedon
was
a
prime
mover
in
the
establishment
of
the
genetic
counselling
scheme.
Many
mem-
bers
of
the
Keeshond
Club,
including
Mr
M.
Stockman
and
Mrs
S.
Scroggs
have
given
helpful
advice,
and
their
interest
and
coopera-
tion
is
greatly
appreciated.
They
and
Dr
J.
G.
Hall
kindly
com-
mented
upon
the
manuscript.
References
BIRD,
T.
D.
(1987)
Epilepsia
28
(Supplement
1),
S71
BIRD,
T.
D.
(1994)
Epilepsia
35
(Supplement
1),
S2
BONNER,
J.
(1994)
New
Scientist
144,
1950,
34
BUCHHALTER,
J.
R.,
(1993)
Epilepsia
34
(Supplement
3),
S31
CROFT,
P.
G.
&
STOCKMAN,
M.
J.
R.
(1964)
Veterinary
Record
76,
261
CUNNINGHAM,
J.
G.
&
FARNBACH,
G.
C.
(1988)
Journal
of
the
American
Animal
Hospital
Association
24,
421
FALCO,
M.
J.
(1975)
Biometrics
31,
993
GATACRE,
A.
(1938)
The
Keeshond.
London,
Country
Life
GRANT,
G.
M.
(1976)
Journal
of
Heredity
67,
393
HELWIG,
J.
T.
&
COUNCIL,
K.
A.
(1979)
SAS
User's
Guide.
Cary,
North
Carolina,
SAS
Institute
KRAMER,
J.
W.,
KLAASSEN,
J.
K.,
BASKIN,
D.
G.,
PRIEUR,
D.
J.,
RANTA-
NEN,
N.
W.,
ROBINETTE,
J.
D.,
GRABER,
W.
R.
&
RASHTI,
L.
(1988)
American
Journal
of
Veterinary
Research
49,
428
NICHOLAS,
F.
W.
(1987)
Veterinary
Genetics.
Oxford,
Clarendon
Press.
p
226
PATTERSON,
D.
F.,
AGUIRRE,
G.
A.,
FYFE,
J.
C.,
GIGER,
U.,
GREEN,
P.
L.,
HASKINS,
M.
E.,
JEZYK,
P.
F.
&
MEYERS-WALLEN,
V.
N.
(1989)
Journal
of
Small
Animal
Practice
30,
127
PATrERSON,
D.
F.,
PEXIEDER,
T.,
SCHNARR,
W.
R.,
NAVRATIL,
T.
&
ALAILI,
R.
(1993)
American
Journal
of
Human
Genetics
52,
388
SPURLING,
N.
W.,
BUTCHERS,
J.,
DAVEY,
A.
J.
&
FORSTER,
K.
(1983)
Zentralblatt
fur
Veterinarmedizin
A
30,
245
WALLACE,
M.
E.,
(I1975)
Journal
of
Small
Animal
Practice
16,
1
WILLIS,
M.
B.
(1989)
Genetics
of
the
Dog.
London,
H.
F.
and
G.
Witherby
Role
of
chronic
disseminated
intravascular
coagulation
in
a
case
of
canine
angiostrongylosis
I.
K.
Ramsey,
J.
D.
Littlewood,
J.
K.
Dunn,
M.
E.
Herrtage
Veterinary
Record
(1996)
138,
360-363
A
dog
whose
major
clinical
signs
suggested
a
coagulopathy,
is
described.
The
dog
had
a
history
of
bleeding
episodes
and
had
a
severe
regenerative
anaemia.
By
using
specific
factor
assays,
the
coagulopathy
was
found
to
be
due
to
a
consumptive
intravascular
process
that
resembled
chronic
disseminated
intravascular
coagulation.
Subsequent
investigations
identi-
fied
Angiostrongylus
vasorum
as
the
cause.
ANGIOSTRONGYLUS
vasorum
is
a
metastrongylid
nematode
that
infects
dogs
and
foxes.
Infestations
are
acquired
by
the
ingestion
of
slugs,
snails
and
frogs
which
serve
as
intermediate
or
paratenic
hosts
for
the
parasite
(Rosen
and
others
1970,
Ubelaker
1986,
Bolt
and
others
1994).
The
life
cycle,
morphology
and
epizootiology
of
A
vasorum
have
recently
been
reviewed
by
Bolt
and
others
(1994).
Angiostrongylosis
has
been
reported
in
many
countries,
but
appears
to
be
particularly
frequent
in
Mediterranean
regions
(Guilhon
1963,
Poli
and
others
1984).
A
vasorum
has
been
report-
ed
in
the
United
Kingdom
in
Cornwall,
south
Wales
and
south
east
England
(Jones
and
others
1980,
Trees
1987,
Cobb
and
Fisher
1990).
The
clinical
signs
of
angiostrongylosis
are
variable.
Coughing,
dyspnoea
and
exercise
intolerance
are
common,
but
a
variety
of
other
signs
that
may
overshadow
the
signs
of
pul-
monary
disease
have
been
recorded
(Dodd
1973,
Perry
and
others
1991,
Koch
and
others
1992,
Martin
and
others
1993,
Patteson
and
others
1993,
King
and
others
1994).
Asymptomatic
animals
I.
K.
Ramsey,
BVSc,
PhD,
CertSAM,
MRCVS,
J.
K.
Dunn,
MA,
BVMS,
MVetSci,
DSAM,
MRCVS,
M.
E.
Herrtage,
MA,
BVSc,
DVD,
DVR,
DSAM,
MRCVS,
Department
of
Clinical
Veterinary
Medicine,
University
of
Cambridge,
Madingley
Road,
Cambridge
CB3
OES
J.
D.
Littlewood,
MA,
BVSc,
DVR,
CertSAD,
PhD,
MRCVS,
Centre
for
Small
Animal
Studies,
Animal
Health
Trust,
PO
Box
5,
Newmarket
CB8
7DW
have
also
been
recorded,
which
suggests
that
the
condition
may
be
more
widespread
than
previously
thought
(Martin
and
others
1993,
Patteson
and
others
1993).
The
pulmonary
lesions
are
thought
to
be
caused
by
a
chronic
inflammatory
reaction
to
the
adult
worms
(Bolt
and
others
1994),
but
the
mechanisms
by
which
the
other
clinical
signs
arise
are
less
clear.
This
paper
describes
a
naturally
occurring
case
of
angio-
strongylosis
whose
major
clinical
signs
were
due
to
a
coagulo-
pathy.
The
underlying
pathogenesis
of
this
haemorrhagic
diathesis
was
found
to
be
chronic
disseminated
intravascular
coagulation.
The
significance
of
this
finding
is
discussed.
Materials
and
methods
Clotting
assays
were
carried
out
in
acid-washed
glass
tubes
kept
at
37°C
in
a
water
bath
as
described
by
Littlewood
(1988).
The
average
whole
blood
clotting
times
were
measured
by
incu-
bating
two
tubes,
each
containing
2
ml
of
the
dog's
blood,
and
gently
inverting
them
every
30
seconds
until
the
samples
clotted.
One-stage
prothrombin
times
were
measured
by
the
addition
of
100
tl
of
resuspended
rabbit
brain
thromboplastin
to
100
,l
of
cit-
rated
plasma,
followed,
three
minutes
later,
by
100
g1
of
25mM
calcium
chloride.
Kaolin-cephalin
clotting
times
were
measured
by
the
addition
of
200
gl
of
a
commercial
kaolin-cephalin
mixture
(Diagen;
Diagnostic
Reagents)
to
100
,ul
of
citrated
plasma,
fol-
lowed,
three
minutes
later,
by
100
gl
of
25mM
calcium
chloride.
Kaolin-cephalin
clotting
times
are
analogous,
though
not
identi-
cal,
to
activated
partial
thromboplastin
times
(Hall
and
Malia
1991).
For
these
tests
samples
of
plasma
obtained
from
healthy
dogs
were
assayed
concurrently
in
the
same
way.
Fibrinogen
was
assayed
by
two
methods.
The
first
method
relied
on
the
difference
in
the
concentration
of
total
protein
(as
measured
by
a
refractometer)
between
a
sample
heated
in
a
water
bath
at
56°C
for
three
minutes
and
a
control
sample.
The
second
method
used
a
commercially
available
test
based
on
the
Clauss
technique
(ThromboTest;
Boehringer
Mannheim).
An
excess
of
360
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doi: 10.1136/vr.138.15.358
1996 138: 358-360Veterinary Record
S. J. G. Hall and M. E. Wallace
programme for keeshonds
Canine epilepsy: a genetic counselling
http://veterinaryrecord.bmj.com/content/138/15/358
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... Many authors claim that the loss of genetic variability and inbreeding contributes to the development of physical diseases, defects, and disorders such as reduced fertility and prolificacy, the occurrence of lethal alleles in a litter, and a lower offspring survival rate. In addition, anomalies may occur in the hip joint anatomy leading to dysplasia among house dogs, especially in large breeds (HALL & WALLACE 1996;UBBINK et al. 1998;ÓLAFSDÓTTIR & KRISTJÁNSSON 2008;KRZEMIÑSKA et al. 2018). Inbreeding coefficients for a breed range from about 0.82% for Golden Retrievers, 2% for German Shepherd Dogs, 4.5% for Bullmastiff Dogs, 6.7% for Bracco Italiano Dogs, through 9% for Great Danes to 26% for Nova Scotia Duck Tolling Retrievers and as much as 37% for Polish Hounds (DROZD & KARPIÑSKI 1997;G£A¯EWSKA 2008;MÄKI 2010;KANIA-GIERDZIEWICZ et al. 2014;CECCHI et al. 2016;MORTLOCK et al. 2016). ...
Article
Full-text available
The aim of the study was the analysis of the structure of the population, relationship coefficients, and inbreeding trends in terms of: sex, breeding system, and inbreeding degree of Tatra Shepherd dogs. The breed's inbreeding rate was 6.34%, and for a standardised 4-generation population was 6.68%. The highest inbreeding rate was found in "non-champion-dogs" and in "Polish dog" groups consisting of males and females. The limit value F X was exceeded for 25.65% of Tatra dogs, and the critical value was exceeded for 11.52%. An increasing ancestor loss coefficient (AVK) was found, which may result in an increased number of inbred animals. In particular, this referred to female dogs in the nCH, PL, and Z groups, whereas a significant increase of AVK was observed in the group of male dogs from foreign kennels. The resulting COR values were 55.58% for males and 55.44% for females.
... Besides, it must be considered that there may be several congenital pathologies at the same time. For such breads as German Shepherd, Beagle (Beagles are especially prone to develop epilepsy), Belgian Sheepdog (Tervuren), dachshund, Horak's laboratory dog, Irish Setter (assumed), German Spitz (Keeshond) genetic causes are typical; for Labrador Retriever, Golden Retriever, Irish Setter, Poodle (Miniature, Standard), St. Bernard -idiopatic causes; for Boston Terrier, Chihuahua, Miniature Pinscher, Toy Poodle, Pekingese, Yorkshire Terrier -hydrocephalus; for Boston Terrier and Boxer -neoplasia; for Lhasa Apso -lissencephaly; for English Setter, German shorthaired pointer -lipodystrophy; for Cairn Terrier, West Highland White Terrier -globoid cell leukodystrophy; for Miniature Schnauzer, Maltese, Yorkshire Terrier -portocaval shunt; for Miniature Schnauzer -hyperlipo-proteinemia; for Cocker Spaniel, Collie, Siberian Husky, Wire Fox Terrier -the high incidence [Holliday 1980, Oliver 1980, Oliver 1987, Hall and Wallace 1996, Famula and Oberbauer 2000, Lorenz and Kornegay 2004. ...
... Most dogs present between one and five years old [2, 7, 11, 66, 75, 83]. The average cat presents at age three-and-a-half [10].This condition is believed to be inherited in the following breeds of dog[2, 11,22,61,70,71,73,76,77,[84][85][86][87][88]: Patients may seize as infrequently as once per year or as often as several times each day [2, ...
Chapter
Seizures occur when bursts of uncontrolled electrical activity translate into motor activity. Seizure activity takes on a variety of presentations, depending upon the patient and the degree to which one or both cerebral hemispheres are involved. Generalized seizures are characterized by whole‐body involvement, collapse, and loss of consciousness. Patients often exhibit extensor rigidity in all four limbs. Limbs also frequently demonstrate paddling behavior. Unconscious behaviors, such as chewing, licking, swallowing, and vocalizing, may emerge during seizure activity. Autonomic signs may also appear. It is not uncommon for patients to lose control over their urinary bladders or bowels. At times, seizures may be difficult to differentiate from syncopal episodes. Thorough history taking may help to distinguish the two. Partial seizures, on the other hand, may resemble dyskinesias. Partial seizures involve one region of one cerebral hemisphere, and may therefore target any part of the body. The neck, trunk, or limbs are most commonly involved. There are many causes of seizures, regardless of whether they are generalized or partial. For ease of consideration, causes of seizure activity may be described as being intra‐ or extracranial. These categories prioritize differentials differently based upon the patient's age. In a pediatric patient, meaning one that is less than one year of age, seizures are most likely due to a developmental defect or traumatic injury. Other common causes of pediatric seizures include hepatic encephalopathy (HE), as from a portosystemic shunt (PSS) or neonatal hypoglycemia. Young adult to middle‐aged patients, on the other hand, are more likely to develop idiopathic epilepsy, as compared to seniors, which are more likely to develop intracranial neoplasia. Most seizures are self‐limiting. However, a fraction of seizures may become protracted, either in terms of their duration or frequency. Cluster seizures occur when the frequency of seizures exceeds two over a 24‐h period. Status epilepticus occurs when either a seizure lasts for more than 5 min, or multiple seizures overlap such that patient recovery time between events is eliminated. Status epilepticus is a medical emergency.
... Idiopathic epilepsy (IE) is one of the most common chronic neurological disorders in dogs, which is defined as a disorder of the brain characterized by spontaneous recurrent epileptic seizures of unknown, genetic or suspected genetic origin [1][2][3]. A genetic component was considered in several breeds [4], especially in Australian Shepherds [5], Beagles [6], Belgian Shepherds [7], Border Collies [8], English Springer Spaniels [9], Golden Retrievers [10], Keeshonds [11], Labrador Retrievers [12], Lagotto Romagnolos [13,14], Viszlas [15] and others. Affected dogs mostly have their first epileptic seizure with an age of 6 months to 6 years, interictal general and neurological examinations are normal [16,17]. ...
Article
Full-text available
Background One of the most common chronic neurological disorders in dogs is idiopathic epilepsy (IE) diagnosed as epilepsy without structural changes in the brain. In the current study the hypothesis should be proven that subtle grey matter changes occur in epileptic dogs. Therefore, magnetic resonance (MR) images of one dog breed (Beagles) were used to obtain an approximately uniform brain shape. Local differences in grey matter volume (GMV) were compared between 5 healthy Beagles and 10 Beagles with spontaneously recurrent seizures (5 dogs with IE and 5 dogs with structural epilepsy (SE)), using voxel-based morphometry (VBM). T1W images of all dogs were prepared using Amira 6.3.0 for brain extraction, FSL 4.1.8 for registration and SPM12 for realignment. After creation of tissue probability maps of cerebrospinal fluid, grey and white matter from control images to segment all extracted brains, GM templates for each group were constructed to normalize brain images for parametric statistical analysis, which was achieved using SPM12. ResultsEpileptic Beagles (IE and SE Beagles) displayed statistically significant reduced GMV in olfactory bulb, cingulate gyrus, hippocampus and cortex, especially in temporal and occipital lobes. Beagles with IE showed statistically significant decreased GMV in olfactory bulb, cortex of parietal and temporal lobe, hippocampus and cingulate gyrus, Beagles with SE mild statistically significant GMV reduction in temporal lobe (p < 0.05; family- wise error correction). Conclusion These results suggest that, as reported in epileptic humans, focal reduction in GMV also occurs in epileptic dogs. Furthermore, the current study shows that VBM analysis represents an excellent method to detect GMV differences of the brain between a healthy dog group and dogs with epileptic syndrome, when MR images of one breed are used.
... A hereditary basis for epilepsy has been documented in several breeds of dogs, including Labrador Retrievers, German Shepherd Dogs, Golden Retrievers, Bernese Mountain Dogs, Belgian Tervurens, Vizslas, Keeshonds, English Springer Spaniels, and Border Collies. [84][85][86][87][88][89][90][91][92][93]95 Although epileptic syndromes with a suspected genetic basis have recently been identified in cats, there is currently insufficient evidence to validate Idiopathic or primary Genetic: seizures are result of a known or presumed genetic defect. Symptomatic or secondary Structural-metabolic: structural or metabolic disease that is confirmed to be associated with an increased risk of developing epilepsy. ...
Article
Objective: To review current knowledge of the etiopathogenesis, diagnosis, and consequences of status epilepticus (SE) in veterinary patients. Data sources: Human and veterinary literature, including clinical and laboratory research and reviews. Etiopathogenesis: Status epilepticus is a common emergency in dogs and cats, and may be the first manifestation of a seizure disorder. It results from the failure of termination of an isolated seizure. Multiple factors are involved in SE, including initiation and maintenance of neuronal excitability, neuronal network synchronization, and brain microenvironmental contributions to ictogenesis. Underlying etiologies of epilepsy and SE in dogs and cats are generally classified as genetic (idiopathic), structural-metabolic, or unknown. Diagnosis: Diagnosis of convulsive SE is usually made based on historical information and the nature of the seizures. Patient specific variables, such as the history, age of seizure onset, and physical and interictal neurological examination findings can help hone the rule out list, and are used to guide selection and prioritization of diagnostic tests. Electroencephalographic monitoring is routinely used in people to diagnose SE and guide patient care decisions, but is infrequently performed in veterinary medicine. Nonconvulsive status epilepticus has been recognized in veterinary patients; routine electroencephalography would aid in the diagnosis of this phenomenon in dogs and cats. Clinical sequelae: Status epilepticus is a medical emergency that can result in life-threatening complications involving the brain and systemic organs. Status epilepticus often requires comprehensive diagnostic testing, treatment with multiple anticonvulsant agents, and intensive supportive care.
... Armaşu et al. (2014) Podell et al. (1995) reported that the diagnosis of idiopathic epilepsy was more probable when the dog experienced the first seizure(s) between 1 and 5 years of age and was a large breed (>15 kg). Viitmaa Hall et al. (1996) reported various breeds. Also, the consensus statement by Hülsmeyer et al. (2015), reviewed all the current evidence available for breeds that have been identified as being predisposed to idiopathic epilepsy with a proven or suspected genetic background. ...
Article
Full-text available
Clinical bottom lineThere remains until recently an overall lack of clarity for the practical criteria for the diagnosis of canine idiopathic epilepsy. Signalment and an interictal neurological examination are vital for the diagnosis of idiopathic epilepsy. Despite the current insufficient evidence, the emerge of new diagnostic methods, such as cerebrospinal fluid and/or serum biomarkers, advanced functional neuroimaging techniques and electroencephalography, is likely to change the diagnostic approach in canine epilepsy in the near future.
... The hereditary component of epilepsy in dogs has been shown in pedigree studies on several breeds. This is the case in Beagles (Bielfelt et al., 1971), German Shepherd Dogs (Falco et al., 1974), Labrador Retrievers , Golden Retrievers (Srenk and Jaggy, 1996), Bernese Mountain Dogs (Kathmann et al., 1999), Belgian Tervuerens (Famula and Oberbauer, 2000), Viszlas (Patterson et al., 2003), Keeshonds (Hall and Wallace, 1996) and English Springer Spaniels (Patterson et al., 2005). Moreover, a mutation in the Epm2b gene has been proven cause in so-called Lafora disease in miniature wirehaired Dachshunds, which is an autosomal, recessive, progressive myoclonic epilepsy. ...
Chapter
Full-text available
As in human medicine, numerous substances that potentiate the effect of GABA on GABAA receptors are commonly used in veterinary medicine. The indications for the use of GABA positive allosteric modulators, among them benzodiazepines and barbiturates, in animals are very similar to those in humans. Benzodiazepines are clinically used as anticonvulsants, behavioral modifiers, premedicaments, anesthesia inducers and adjuvants in neuroleptanalgesia. Barbiturates are used as anesthetics, anticonvulsants and as euthanasia agents. Sometimes these drugs are administered in combination, mostly for anesthesia or for behavior modification, e.g. for thunderstorm phobia in dogs. Although neither the FDA nor the EMA have approved benzodiazepines for the use in animals, their clinical use in veterinary medicine is increasing, especially for various behavioral disorders. Due to their closeness to humans, companion animals, such as dogs and cats, are frequently diagnosed for separation anxiety, depression and various displacement and self-directed behaviors, which is followed by increased prescription and use of benzodiazepines. Benzodiazepines and barbiturates are considered valuable in veterinary practice, but one must always take into consideration their species-specific pharmacological properties, with the emphasis on adverse reactions and side effects: short-term memory and learning impairment, ataxia, lethargy, somnolence, addiction, paradoxical excitement, anxiety, aggression, excessive vocalization, sleep disturbances, transient apnea, and respiratory and cardiovascular depression. Moreover, it should be noted that severe untoward effects are described within literature, e.g. idiosyncratic hepatotoxicity has been reported following diazepam administration in cats as well as during phenobarbital treatment in dogs.
Preprint
Full-text available
The aim of the study was to analyse the structure of the population, kinship coefficients and inbreeding trend taking into account the sex, breeding system: champions (CH) and non-champions (nCH), breeding country: Poland (PL) and foreign country (Z) and the inbreeding degree of Tatra Shepherd dogs. Out of the currently registered 587 Tatra Shepherd dogs, 41.9% have been qualified for breeding. In the past decade, 1961 puppies were born, which corresponds to an average litter of 5.8 puppies. The breed's inbreeding rate amounted to 6.34%, and for a 4-generation population was 6.68%. The highest inbreeding rate was found in nCH and PL groups consisting of both male and female dogs. The inbreeding rate was significantly higher in 2005-2014 compared to the years 1994-2004. The limit value F X was exceeded for 25.65% of Shepherd dogs, and the critical value was exceeded for 11.52%. An increasing ancestor loss coefficient (AVK) was found, which may result in an increased number of inbred animals. In particular, it referred to female dogs in the nCH, PL, and F group, whereas a significant increase of AVK was observed in the group of male dogs from foreign kennels. The resulting COR values, respectively 55.58% for males and 55.44% for females, testify to insignificant inbreeding and suggest that breeders look for male inbreds. Studies have shown that there is no risk of inbred depression yet; however, the gene pool of the Tatra Shepherd dog breed has become noticeably restricted. In addition, leaving the stud book for the breed open must be considered due to an increase in the popularity of the breed, and thus an increase in mating.
Article
Brief details are given of a computer program for calculating inbreeding coefficients.
Article
A simple procedure is described whereby both a priori and a posteriori pedigree data, together with a relevant laboratory analytical value, can be utilised in the calculation, for any individual in a defined population, of a single index expressing the probability of heterozygosity for a particular autosomally inherited recessive defect. An hereditary disorder of the blood coagulation system, factor-VII deficiency (hypoproconvertinaemia), in Beagles was used as the model for this project. Beurteilung der Heterozygotie-Wahrscheinlichkeit (Phet) für ein einzelnes autosomales rezessives Merkmal bei Beagles: Ein Gesamtindex für Phet unter Einbeziehung von Abstammung und Labordaten Ein einfaches Verfahren wird beschrieben, in welchem sowohl die Daten der Ahnen als auch der Nachkommen zusammen mit einem relevanten analytischen Laboratoriumswert zur Berechnung eines einzelnen Index verwendet werden. Dieser Index kann für jedes Individuum in einer definierten Population berechnet werden, um die Heterozygotie-Wahrscheinlichkeit für einen bestimmten hereditären rezessiven Defekt zu schätzen. Als Modell für dieses Projekt diente eine erbliche Störung des Blutgerinnungssystems, die Faktor-VII-Insuffizienz (Hypoproconvertinämie) bei Beagles. Evaluation de la probabilité d'hétérozygotie (Phet) pour un caractère récessif autosome unique: un index unique pour Phet comprenant le pedigree et les données de laboratoire Un procédé simple est décrit dans lequel les données des ancêtres aussi bien que celles des descendants sont untilisées en même temps qu'une valeur analytique significative de laboratoire pour calculer un index unique. Cet index peut être calculé pour chaque individu dans une population définie afin d'estimer la probabilité d'hétérozygotie pour un défaut récessif déterminé et héréditaire. Un trouble héréditaire du système de coagulation sanguine, l'insuffisance du facteur VII (hypoproconvertinémie) chez des Beagles, a servi de modèle pour ce projet. Evaluación de la probabilidad de heterozigocia (Phet) para una característica autosómica recesiva única: un indice simple de Phet incorporando la genealogía y los datos de laboratorio Se describe un procedimiento simple, en el cual se utilizan tanto los datos genealógicos a priori como los a posteriori, junto con un valor analítico relevante de laboratorio para calcular un índice único. Este índice se puede calcular para cada individuo en una población definida, para valuar la probabilidad de heterozigocia para un defecto hereditario autosómico recesivo determinado. Como modelo para este proyecto sirvió un trastorno hereditario en el sistema de coagulación de la sangre, la deficiencia del factor VII (hipoproconvertinemia) en los beagles.
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Data are presented from some 321 Keeshond dogs attending a clinic for electroencephalographic records, and their 108 close ancestors. They are examined to see whether the EEG readings are diagnostic of a tendency to epileptiform fits, and what hereditary basis there is, if any, for both the readings and the fits. The evidence does not support the idea of a diagnostic value; finds no hereditary basis for the readings; and, as far as the limited information about dogs which have had fits allows, slightly favours some hereditary component in the aetiology of epilepsy. These findings are discussed in relation to those concerning hereditary epilepsy in other breeds.
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Where the occurrence of homozygous recessives and heterozygotes is known in the pedigrees of prospective sires and dams, a method and appropriate tables are given to predict the minimum probability 1) that progeny will be homozygous recessive, or 2) that progeny of dominant phenotype are heterozygous.
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This report reviews various lines of evidence demonstrating important genetic influences in the epilepsies, with special emphasis on childhood epilepsy. Five pertinent topics are discussed: (a) examples of domina