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Objectives of the Presentation
To give
an update on the latest information regarding the clinical
signs of Idiopathic Epilepsy in dogs.
To give
an update on the latest information regarding the genetics
of Idiopathic Epilepsy in dogs.
To give
basic information related to trying to control IE in dog
breeding until the time in which specific breeds have
conclusive genetic tests.
To
encourage veterinarians, breeders and owners to submit
samples of dogs with Idiopathic Epilepsy and their close
relatives to institutions conducting research.
Overview of the Issue
Idiopathic Epilepsy is repeated
seizures over time in which an underlying cause is not
determined. Typically dogs affected with IE have their first
seizure from 6 months to 6 years of age. Most IE is
considered to have a genetic basis and is a difficult for
breeders to select against because of the late onset of the
disease and the lack of identification of carriers. The
lifetime incidence of Idiopathic Epilepsy (IE) in dogs is
reported to be from 0.5% to 5% depending on the breed (Podell
1995). Often an affected dog has already been bred before
the condition is diagnosed. Inherited forms of IE are
currently known to exist in many different dog breeds
although to date the genetic bases have not yet been
determined. For the breeds in which there have been
scientific studies of the mode of inheritance, it has been
suggested to be either simple recessive or polygenic
recessive inheritance. Under both types of inheritance
canine epilepsy is a difficult trait to control based on
phenotype alone, since it can be also be passed on by
carrier animals that are not themselves clinically affected.
Summary
Many inherited diseases in breeds of
dogs are caused by a "founder" effect, which is also the
basis of many genetic diseases found in isolated human
populations. Inherited or idiopathic epilepsy (IE) is a
common canine disease causing repeated seizures and is the
most common neurological disease of dog and is the one of
the top 3 overall health concern for many dog breeds (AKC
Survey 2001). IE must be differentiated from secondary
epilepsy in which there is an underlying cause such as brain
tumor, brain malformation, brain infection, low blood sugar,
low blood calcium, or liver failure. A search of idiopathic
epilepsy diagnoses from all contributing North American
Veterinary Colleges was performed by comparing breed, age,
and sex of all first time canine admissions for epilepsy in
a specific breed versus all admissions for that specific
breed from 1987 to 1997. Overall, the percentage of epilepsy
admissions by breed ranged from 0.12% to 2.01% with an
all-breed average, including mixed breeds, of 0.82% (Table
1).
Table 1 - Percentage of First Times
Admissions by Breed for Canine Idiopathic Epilepsy
Breed |
% |
All |
0.82 |
Border Collie |
2.01 |
Schipperke |
1.98 |
Saint Bernard |
1.92 |
Germ SHP |
1.78 |
Keeshond |
1.72 |
Irish Setter |
1.68 |
Siberian Husky |
1.63 |
Pug |
1.45 |
English Springer |
1.30 |
Dalmatian |
1.28 |
American Eskimo |
1.25 |
Giant Schnauzer |
1.23 |
Shetland Sheep |
1.20 |
Golden Retriever |
1.20 |
Vizsla |
1.17 |
Belgian Sheepdog |
1.16 |
Boston Terrier |
1.16 |
Poodle - Min |
1.15 |
Jack Russell |
1.14 |
Belgian Tervuren |
1.13 |
Brittany Spaniel |
1.09 |
Poodle - Toy |
1.09 |
Poodle standard |
1.07 |
Norwegian Elkhound |
1.03 |
Bernese Mountain |
1.02 |
Welsh Terrier |
1.02 |
Chesapeake Bay |
0.98 |
Std Schnauzer |
0.96 |
German Shepherd |
0.95 |
Dachshund long |
0.95 |
Schnauzer - mini |
0.94 |
Alaskan Malamute |
0.93 |
Australian Shep |
0.93 |
Pomeranian |
0.87 |
Pekinese |
0.86 |
Scottish Terrier - |
0.85 |
Germ Wire HP |
0.83 |
Lhasa Apso |
0.83 |
Mini Pinscher |
0.83 |
Great Pyrenees |
0.82 |
Welsh Corgi |
0.82 |
Mixed Breed |
0.81 |
American Cocker |
0.81 |
Blood hound |
0.81 |
Labrador Retriever |
0.80 |
Weimaraner |
0.79 |
Basenji |
0.77 |
Rhodesian Ridge |
0.76 |
Maltese |
0.75 |
Fox Terrier |
0.74 |
Boxer |
0.74 |
Beagle |
0.73 |
Collie |
0.71 |
Yorkshire Terrier |
0.71 |
Mastiff |
0.71 |
Cairn Terrier |
0.71 |
Chihuahua |
0.70 |
Borzoi |
0.69 |
Aust Cattle Dog |
0.67 |
Dachshund, mini |
0.67 |
Welsh Corgi |
0.66 |
Whippet |
0.65 |
Engl Cocker Span |
0.65 |
Airedale Terrier |
0.61 |
Basset Hound |
0.60 |
Black/ Tan Coon |
0.59 |
English Setter |
0.57 |
Shih Tzu |
0.52 |
Great Dane |
0.52 |
Bulldog |
0.50 |
Bedlington Terrier |
0.50 |
Border Terrier |
0.48 |
Bull Terrier |
0.46 |
Fox Terrier Toy |
0.45 |
Bichon Frise |
0.45 |
Silky Terrier |
0.45 |
Samoyed |
0.44 |
Flat Coat Retriever |
0.44 |
Dachshund |
0.41 |
Akita |
0.40 |
Shar-pei |
0.38 |
Afghan Hound |
0.38 |
West Highland Terr |
0.37 |
Greyhound |
0.37 |
Irish Wolfhound |
0.29 |
Doberman Pins |
0.28 |
Am Staff Terrier |
0.27 |
Rottweiler |
0.26 |
Pointer |
0.26 |
Old Engl Sheep |
0.26 |
Newfoundland |
0.25 |
Bouvier Des Fland |
0.25 |
Chow Chow |
0.19 |
Gordon Setter |
0.19 |
Soft Wheaton |
0.13 |
Bullmastiff |
0.12 |
Peer-reviewed scientific studies
indicating a genetic basis for idiopathic epilepsy are
available for Beagles (Bielfelt 1971), German Shepherds
(Falco 1974), Keeshonds (Hall 1996), Dachshunds (Oliver
1994), Golden Retrievers (Srenk 1994), Labrador Retrievers
(Leinweiner 1999), Bernese Mountain Dogs (Kathmann 1999),
Vizslas (Patterson 2003), Belgian Tervurens (Oberbauer
2003), and English Springer Spaniels (Patterson 2005). These
publications have indicated possible modes of inheritance of
IE, but the molecular bases are unknown at this time. A
brief summary of the variety of known seizure
characteristics and suggested modes of inheritance of canine
epilepsy is presented in Table 2.
Table 2.
Breed |
Seizure characteristics |
Genetic basis |
Sex influenced |
Reference |
Beagle |
Partial and generalized |
Significant sire effect |
Bias towards males |
Bielfelt et al., 1971 |
German Shepherd Dog |
|
Significant sire effect |
Bias towards males |
Falco, 1974 |
Keeshonds |
|
Suspected recessive |
No bias |
Hall and Wallace, 1996 |
Golden Retriever |
Mostly generalized |
Polygenic autosomal
recessive |
Bias towards males |
Srenk et al., 1994 |
Labrador Retriever |
Most generalized |
Polygenic autosomal
recessive |
No bias |
Jaggy et al., 1998 |
Bernese Mountain Dog |
Mostly generalized |
Polygenic autosomal
recessive |
Bias towards males |
Kathmann et al., 1999 |
Belgium Tervuren and
Sheepdog |
Generalized |
Locus of large effect |
No bias |
Oberbauer at el., 2003 |
Vizsla |
Most partial and some
generalized |
Consistent with autosomal
recessive; polygenic possible |
No bias |
Patterson et al., 2003 |
English Springer Spaniel |
Both generalized and focal
onset |
Partially penetrant
autosomal recessive or polygenic |
No bias |
Patterson et al., 2005 |
It is very likely that many more
breeds have heritable forms of IE but insufficient data has
yet been collected to characterize it. The multiple modes of
inheritance identified in the studies to date, as well as
the diverse nature of the breeds involved, make it highly
likely that there will be many different genetic causes for
canine epilepsy. It is possible, though, that related breeds
with similar IE phenotypes may have a similar genetic basis.
The only anti-epileptic drugs that are
consistently effective in dogs are phenobarbital and bromide
(Podell 1996). Euthanasia may be chosen due to frequency or
severity of seizures in cases in which these drugs are not
effective.
There is some controversy in the
veterinary community regarding partial seizures in dogs and
the cause of the seizure disorder (idiopathic versus
secondary). By definition, a partial seizure originates in a
small region of the brain. A generalized (grand-mal type)
originates simultaneously in most of the outer parts of the
brain. Some authors believe that partial seizures are likely
to indicate an underlying structural brain abnormality
(Berendt 1999, Knowles 1998), whereas others believe that
partial seizures can have a heritable basis with no
underlying brain abnormality and therefore be considered IE
(Thomas 2000, Podell 1996). A recent study classified 65% of
epileptic dogs as having partial onset seizures and 32% as
having primary generalized (grand-mal type) seizures
(Berendt 1999).
In our analysis of seizures in Vizslas
(Patterson 2003) seventy-nine percent of the dogs affected
with IE had partial seizures with or without secondary
generalization. Partial seizure signs consisted of a
combination of leg tremors, staring, dilated pupils,
salivation, or some combination of these without loss of
consciousness in over 79% of the affected individuals. Thus,
there is increasing evidence that partial seizures, in which
the seizures start in the age range of 6 months to 6 years
of age, are often heritable in dogs and therefore can be
classified as IE.
Epilepsy also affects approximately 1%
of the human population, and the causative mutations in 22
very rare forms of human IE have been recently reported
(Gurnett 2007). However, the most common idiopathic human
epilepsies have complex (polygenic) inheritance (Berkovic
1999). Since 15 of the 22 genes currently identified as
causative of human IE are ion channels sodium (Na+),
potassium (K+), calcium (Ca++), and chloride (Cl-) -
(Gurnett 2007), it is suspected that ion channel defects may
be involved in the more common polygenic forms of IE in
people (Steinlan 1998), and could possibly be involved in
canine epilepsy. However, there are hundreds of different
potassium, chloride, sodium, and calcium channels, often
with multiple sub-units, expressed in the brain(Lehmann-Horn
1999). Given the complex mechanisms regulating excitability
in the brain it is likely that hundreds of genes could
potentially cause IE.
There are a number of ongoing projects
trying to determine the gene or genes that cause IE in
various dog breeds at the University of Minnesota, the
University of Missouri -Columbia, The University of
California - Davis, The University of Toronto, The Animal
Health Trust in England, A University in Finland, and at a
few other institutions.
|
|
Figure 3. Pedigree
indicating relationships of 29 Vizslas affected with
IE.
xxxx indicates 3 common sires that are
all related to one common sire (not shown) within 3
or 4 generations. (from Patterson 2003). |
In our lab, we have made the most
progress in Vizslas. To date, we have collected 86 affected
Vizslas and 606 related family members. In 2003, we
published an initial analysis of 29 affected Vizslas,
indicating that most Vizslas have partial onset seizures and
that the mode of inheritance is consistent with autosomal
recessive (table 3), but that polygenic inheritance is also
possible (Patterson 2003).
We have checked 448 DNA markers over
all 39 canine chromosomes for our entire collection of
Vizsla families. We have excluded approximately 92% of the
genome from containing an epilepsy gene based on the
possible simple recessive inheritance. We currently have
found 3 markers with suggestive but not conclusive linkage
(association) to IE in Vizslas on one specific canine
chromosome.
We have also used another strategy for
finding genes for IE in Vizslas. As mentioned, Ion channels
(Na+, CA++, K+, Cl- etc) have been found to cause epilepsy
in 15 of 22 mutations defined in isolated human populations.
We have now identified 50 unpublished microsatellite markers
near Ca++ channels, Na+ channels, K+ channels, GABA and
Acetycholine receptor ion channels and have checked our
Vizsla family collection with them. In the past 14 months,
genetic analysis of 18 Ca++ channels, 12 K+ channels, and 8
NA+ channels have excluded them as being a causative gene
for IE in these Vizslas families. We are continuing to test
the remaining genes at this time.
In addition we have tested a number of
affected Vizslas for the mutation causing progressive
myoclonic epilepsy (Lafora Disease) in Dachshunds (Lohi et
al. 2005) and none of these affected Vizslas have this
particular mutation.
In summary, to date we have tested 486
genetic markers on our Vizsla samples. We have identified a
possible area for a Vizsla IE gene in a small span of canine
one specific canine chromosome. This Chromosome span is
likely to contain a gene contributing to Epilepsy in Vizslas
and we are studying additional markers in the area. We are
concerned, however, that IE in Vizslas could be controlled
by two or more genes that would be unlikely to be detected
with our current methods. We plan on next using thousands of
single nucleotide polymorphism (SNP) based genetic markers
that have just been developed. These SNP markers have the
potential to detect chromosomal areas for complex genetic
traits in which 2 or more genes cause a disease.
Since the most common mode of
inheritance for IE in dogs is either simple autosomal
recessive or polygenic recessive it will be very difficult
to eliminate carriers from breeding until conclusive genetic
tests are developed. Given emerging DNA technology for dogs,
in a few dog breeds genetic mutations are likely to be
identified in the next 3-5 years. Given, that different
breeds (unless closely related) are likely to have different
genes involved, it may be many more years until conclusive
genetic tests are developed in some other breeds.
If a breeder is having difficulty
which IE in their lines, the best that can be done for now
is to have a canine geneticist do carrier risk analysis for
those breeds in which IE has been suggested to be simple
autosomal recessive (Table 2). For breeds in which IE has
been suggested to be polygenic or breeds in which the
inheritance is unknown then depth and breadth of pedigree
analysis should be done (as is done for other polygenic
traits such as hip dysplasia) with the recommendation that
no ancestors in the depth of pedigree are affected with IE,
and that <25% of siblings are affected with IE in the
breadth of pedigree analysis. In addition for lines with an
IE problem it is suggested that one or both of the breeding
individuals also be at least 5 years of age in order for it
to be likely that they are not affected with IE. Once
conclusive genetic tests are developed for a breed then
breeding recommendations will be much more concrete, and
more likely to rapidly decrease the incidence of IE.
To help these studies progress we
encourage individuals to submit DNA of purebred dogs
affected with IE and their close relatives to the various
studies. In the case where more than one group is studying
the same breed, I recommend individuals submit samples to
all groups performing the studies.
References/Suggested Reading
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and seizure classification in 63 dogs: a reappraisal of
veterinary epilepsy terminology. J Vet Intern Med 13:14-20.
2. Berkovic, S. F., and Scheffer, I.
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3. Bielfelt SW, Redman HC, McClellan
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epileptiform seizures in a purebred beagle dog colony. Am J
Vet Res. 32: 2039-2048.
4. Falco, M.J., Barker J., and
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Canine epilepsy: a genetic counseling programme for
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