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Topical Review
Inherited Epilepsy in Dogs
Kari J. Ekenstedt, DVM, PhD
a,
n
, Anita M. Oberbauer, PhD
b
Keywords:
dog
epilepsy
gene
inheritance
seizures
progressive myoclonic epilepsy
a
Department of Animal and Food Science,
College of Agriculture, Food, and
Environmental Sciences, University of
Wisconsin –River Falls, River Falls, WI, USA
b
Department of Animal Science, College of
Agricultural and Environmental Sciences,
University of California, Davis, CA, USA
n
Address reprint requests to Kari J.
Ekenstedt, University of Wisconsin—River
Falls, 246 Agriculture Science Building, 410
South Third Street, River Falls, WI 54022,
USA.
E-mail: kari.ekenstedt@uwrf.edu,
eken0003@umn.edu (K.J. Ekenstedt)
Epilepsy is the most common neurologic disease in dogs and many forms are considered to have a
genetic basis. In contrast, some seizure disorders are also heritable, but are not technically defined as
epilepsy. Investigation of true canine epilepsies has uncovered genetic associations in some cases,
however, many remain unexplained. Gene mutations have been described for 2 forms of canine
epilepsy: primary epilepsy (PE) and progressive myoclonic epilepsies. To date, 9 genes have been
described to underlie progressive myoclonic epilepsies in several dog breeds. Investigations into genetic
PE have been less successful, with only 1 causative gene described. Genetic testing as an aid to diagnosis,
prognosis, and breeding decisions is available for these 10 forms. Additional studies utilizing genome-
wide tools have identified PE loci of interest; however, specific genetic tests are not yet developed. Many
studies of dog breeds with PE have failed to identify genes or loci of interest, suggesting that, similar to
what is seen in many human genetic epilepsies, inheritance is likely complex, involving several or many
genes, and reflective of environmental interactions. An individual dog's response to therapeutic
intervention for epilepsy may also be genetically complex. Although the field of inherited epilepsy
has faced challenges, particularly with PE, newer technologies contribute to further advances.
&2013 Elsevier Inc. All rights reserved.
Introduction
Epilepsy is the most common chronic neurologic disorder in
dogs, reported at a prevalence of between 0.5% and 5% in a
nonreferral population,
1
and humans, where it is estimated to
affect 1%-3% of the population.
2
However, epilepsy is not a single
disease but a group of disorders characterized by a broad array of
clinical signs, age of onset, and underlying causes. The Interna-
tional League Against Epilepsy classifies human epilepsies and
defines terminology for the various etiologies; these terminologies
are as follows: (1) genetic (or primary), (2) structural/metabolic
(including symptomatic), and (3) unknown, in which the mecha-
nistic basis is not yet elucidated.
3
The proposed canine classifica-
tion for epilepsy is a slight modification of that by the
International League Against Epilepsy: (1) primary/genetic epi-
lepsy (often termed “idiopathic”epilepsy), (2) structural epilepsy
(symptomatic epilepsies resulting from structural brain abnormal-
ities), (3) reactive seizures (symptomatic epilepsies resulting from
metabolic or toxic abnormalities), and (4) unknown. Some epi-
lepsies bridge these categories; for example, genetic mutations
may be the cause of a metabolic abnormality that results in
epilepsy. Owing to clinical presentation, these epilepsies are still
classified as metabolic, despite the genetic cause of their disorder.
When chronic, recurring seizures occur and no underlying abnor-
mality is detected, the syndrome is classified typically as primary
epilepsy (PE) and presumed to be genetically regulated. Indeed, in
humans, primary (or idiopathic) epilepsy is generally accepted to
have an underlying genetic origin.
4
Genetic epilepsies have been studied extensively in humans
and mice, and, although an in-depth review of these species has
not been undertaken in this article, it is worth noting that many
parallels exist between syndromes in humans, mice, and dogs. In
humans, genes underlying several rare, monogenic mendelian
genetic epilepsies have been identified. Many are categorized as
“ion channelopathies,”with mutations in genes encoding sodium,
calcium, potassium, and chloride ion channels. Causal mutations
have also been observed in other genes involved in neuronal
signaling, including neurotransmitter receptor genes, such as
gamma-aminobutyric acid receptors or acetylcholine receptors. A
small number of non–ion channel genes, previously unknown to be
involved in the neural system, have also been implicated. Additional
details on these known human genetic epilepsy mutations can be
found in reviews.
4-10
Despite these discoveries, most of the human
genetic epilepsies remain unsolved at the molecular level, and
although most appear to have a strong genetic basis, their inher-
itance patterns are complex, with many contributing genetic and
environmental factors. Greater than 95% of human non-mendelian
epilepsies appear to be complexly inherited.
11
Genome-wide inves-
tigations have failed to uncover major regulatory locisuggesting that
the underlying cause includes both rare and common allele variants
each contributing small effects that may confer risk or protection for
epilepsy.
12
Great interest exists to identify casual mutations to
reduce the risk of epilepsy or inform and improve therapies.
Dozens of epileptic mouse models exist, each representing
different causative mutations. A few represent spontaneous muta-
tions, though most have been engineered intentionally.
13,14
As is
the case for humans, many of these are ion channels genes,
although non–ion channel genes can also underlie single gene
murine epilepsy. For complexly inherited epilepsy, the epilepsy-
like mouse strain suffers seizures in response to physical stimuli,
such as moving a mouse from one cage to another.
15
The epilepsy-
like mouse exhibits a polygenic complex phenotype and has at
1527-3369/$- see front matter &2013 Topics in Companion Animal Medicine. Published by Elsevier Inc.
http://dx.doi.org/10.1053/j.tcam.2013.07.001
Topics in Compan An Med 28 (2013) 51–58
least 6 different loci apparently contributing to seizure suscepti-
bility, indicating gene interactions, locus heterogeneity, and gene-
by-environment interactions.
16-19
Recently the dog has received much attention as a model
organism for the discovery of the molecular mechanisms under-
lying genetic diseases in humans. The unique features that make
the canine species so tractable to the study of inherited conditions
include significant intrabreed homogeneity and sizeable inter-
breed heterogeneity.
20
A popular sire or founder effect observed
in many breeds also contributes to intrabreed homogeneity,
possibly rendering the genetic basis for diseases such as epilepsy
less complex in dogs than humans.
21,22
Thus, relatively inbred dog
populations that have naturally occurring epilepsy segregating
within a breed may prove a relevant model for human genetic
epilepsies. Investigations of canine epilepsy may be superior at
identifying genetic underpinnings when compared with similar
studies in humans, which are plagued by locus heterogeneity, or
mouse models with discrete mutations. The dog model for PE was
predicted to permit the identification of novel genes involved in
central nervous system function. To some degree, this has proven
true as genes have now been identified for several reactive
(symptomatic metabolic) epilepsies and 1 PE in dogs. However,
canine epilepsy, similar to its human counterpart, remains plagued
with complex and difficult-to-elucidate inheritance. The present
review discusses dog breeds suggested to have inherited PEs,
describes the known canine epilepsy genes, details suggestive
genes or loci involved in PE, and briefly, presents pharmacogenetic
investigations of how canine epilepsy responds to drug therapies.
Breeds With Clinical Descriptions of Inherited PEs
Primary (genetic) epilepsies in dogs are a diagnosis of exclusion,
where history, physical and neurologic examinations, blood chem-
istry tests, brain imaging, and cerebral spinal fluid analysis have ruled
out other causes of recurrent seizure activity. Most canine patients
with PE are entirely normal between seizure episodes,
23
although
some may express mild abnormalities, such as episodic ataxia,
between seizures.
24
Although the general prevalence of PE in dogs
is typically considered to be 0.5%-5%,
1
itcanbemuchhigherwithina
single breed. For example, in the Belgian Shepherd, the prevalence
has been estimated from 9.5%-33%
25
in 1 extended family.
26
The
hereditary basis of PE in many breeds is supported by a growing body
of literature,
27
and PE has been reported in nearly every breed as well
as in mixed breed dogs, with the latter having a prevalence of 0.91%
in a study of approximately 90,000 dogs.
28
A recent study examining
over 1200 PE cases from nearly 80 pedigree breeds and mixed breed
dogs observed that the mixed breed dogs comprised the largest
percentage of their cohort (20.5%), with Labrador retrievers as the
next highest (11.0%).
29
This epidemiologic study also observed a
significant overrepresentation of males in the epileptic cohort, com-
pared with a geographically similar nonepileptic control group.
Many breeds with a high prevalence of PE have had their epilepsy
characterized, with descriptions of the clinical phenotype and
suggestions for potential modes of inheritance based on pedigree
relationships. Tabl e 1 lists those breeds identified as having a genetic
or familial basis to PE. To date, 1 PE gene mutation (in the Lagotto
Romagnolo) and 1 associated locus (in the Belgian Shepherd) have
been described and are discussed in more detail later in the article.
Many additional breeds are subjects of PE genetic investigations, and
their PE is suggested to be inherited, but clinical descriptions or
putativemodesofinheritancehavenotbeenpublished.
Other breeds lack sufficient information to definitively classify
their condition as PE or even as an inherited epilepsy syndrome.
For example, the Finnish Spitz is reported to have a genetic
epilepsy,
51,52
but pedigree analysis has not been conducted and
a possible mode of inheritance has not been reported. The Shet-
land Sheepdog has an epilepsy syndrome inherited in a multi-
factorial or autosomal dominant fashion although affected dogs
also have histopathologic changes in their brain tissue.
53
It is
unknown if those lesions represent primary pathology that
induced seizures or if the lesions were a consequence of the
seizures; in case of the latter, this would certainly be classified as
PE. Lastly, a study of Boxers calculated medium-to-high heritabil-
ity estimates for epilepsy in that breed.
54
However, the report did
not indicate that the epilepsy cases underwent thorough testing
and follow-up to sufficiently rule out nonheritable causes of
seizures, creating some uncertainty about the diagnosis of PE.
Among the published PE studies that examined the mode of
inheritance, many breeds showed evidence for autosomal reces-
sive inheritance. Yet, many of those studies could not rule out
polygenic inheritance (Table 1), suggesting the genetic basis for PE
may be quite complicated within dogs. Complex inheritance is
further supported by the observed variability in seizure pheno-
type. For example, the epileptic condition may manifest as
generalized seizures from the onset, focal onset only, or focal
onset progressing to generalized seizures. Likewise, the frequency
of cluster seizures, status epilepticus, and response to antiepileptic
drugs (AEDs) (i.e., success in managing seizures) also vary
between breeds. Taken together, is has become increasingly clear
that, as in humans and even some mouse models, multiple PE loci
exist in dogs. In addition, it is probable that within a breed, more
than 1 locus is causal for the varied PE phenotypes expressed.
Known Genetic Epilepsy Genes—PE
Only 1 mutation causing PE has been described to date (Table 2).
The Lagotto Romagnolo breed segregates a recessive benign familial
epilepsy, which typically remits by 4 months of age.
24
The mutated
gene underlying PE in this breed is a truncating mutation in LGI2,an
ortholog of the human epilepsy gene LGI1.
55
The LGI proteins are
critical in synaptic function. The developmental stage–specific
expression of LGI1 and LGI2, both acting on a-disintegrin-and-
metalloproteinase (ADAM) receptors, appears to protect the brain
during the pruning phase of postnatal neuronal development. The
discovery of the mutation in Lagotto Romagnolo was the first canine
epilepsy mutation described for any PE and revealed a novel
molecular pathway involved in epilepsy.
Progress in identifying additional canine PE genes has been
slow. Candidate gene and genome-wide association (GWA) studies
have identified associations between PE and specific genes or
chromosomal loci, although none appears to be causative nor are
they available as genetic tests. The lack of definitively causal
mutations underscores the multifactorial nature of the condition;
this has been discussed in greater detail later.
Known Genetic Epilepsy Genes—Reactive Epilepsy
Progressive myoclonic epilepsies (PMEs) are reactive seizures
caused by metabolic abnormalities. They are a group of clinically
and genetically heterogeneous, severe, and intractable disorders
characterized by epilepsy, myoclonous, and progressive neurologic
deterioration. Dogs affected with PMEs often have abnormal men-
tation between seizures, measurable abnormal metabolites, and
histopathologic abnormalities that may be observed on postmor-
tem analysis.
In contrast to PE, considerable progress has been made in
identifying the mutations underlying canine PMEs; to date, 9 genes
have been described for reactive (metabolic) epilepsy in dogs. The
first canine metabolic epilepsy mutation to be described was for
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 51–5852
Lafora disease in the miniature wirehaired Dachshund.
56
This
autosomal recessive disease is the result of a biallelic expansion
of a dodecamer repeat in the EPM2B gene. Lafora disease is also
observed in humans and mutations have been described in the
laforin (EPM2A) gene
66
and the malin gene, (NHLRC1, also called
EPM2B),
67,68
the latter being orthologous to the gene mutated in
miniature wirehaired Dachshunds. Lafora disease is characterized
by histopathologic changes consisting of intracellular Lafora
bodies in multiple tissues, including brain, muscle, liver, and
heart.
68,69
This is a clear demonstration of mutations in the same
gene creating similar disease in different species. In another breed,
a case report described Lafora disease in a single Beagle, although
the presence of the expansion mutation was not assessed.
70
Most successful have been the investigations of neuronal
ceroid-lipofuscinoses (NCLs) for which 8 genes have been identi-
fied, all with autosomal recessive inheritance (summarized in
Table 1
Seizure Characteristic in Breeds With Clinical Descriptions of Potentially Inherited Primary Epilepsy
Breed*Seizure Characteristics Age of Onset Genetic Basis Sex Influence References
Australian shepherd Generalized, some with focal onset, some
with secondary generalization
Under 5 y Hereditary basis Bias toward
males
30
Beagle Partial and generalized 1 y minimum Significant sire effect Bias toward
males
31
Belgian Shepherd Most focal onset, some with secondary
generalization
Mean of 3.3 y Simple mendelian, likely autosomal No bias 26
Belgian Shepherd Generalized Mean of 4 y Polygenic No bias 32
Belgian Tervueren Not reported Widely variable Hereditary basis, single-locus models not adequate
to explain
No bias 33
Belgian Tervueren Not reported Not reported Suspected single locus of large effect, with complex
pattern of inheritance
No bias 34
Belgian Tervueren
and Sheepdog
Generalized Not reported Polygenic No bias 35
Bernese Mountain
Dog
Most generalized 1-3 y Polygenic autosomal recessive, sex modified Bias toward
males
36
Border Collie Generalized, many with initial focal onset Under 5 y Autosomal recessive or more complex and
resembling recessive
No bias 37
Dalmatian Most partial onset with secondary
generalization
3 y Not determined Slight bias
toward
females
38
English Springer
Spaniel
Partial and generalized Under 6 y Partially penetrant autosomal recessive or polygenic No bias 39
German Shepherd
Dog (British
Alsatian)
Not reported 1-2 y Sire effect and affected dogs more inbred Bias toward
males
40
Golden Retriever Most generalized 1-3 y Polygenic autosomal recessive Bias toward
males
41
Irish Wolfhound Generalized Under 3 y Incompletely penetrant recessive, with sex
predilection
Bias toward
males
42
Keeshond Not reported 1 y minimum Hereditary basis Bias toward
males
43
Keeshond Not reported Not reported Suspected single autosomal recessive No bias 44
Labrador Retriever Most generalized with possible partial onset 1-3 y Polygenic autosomal recessive No bias 45
Labrador Retriever Partial and generalized Under 4 y Not determined No bias 46
Lagotto Romagnolo Varies, with some simple focal and others
complex focal or secondarily generalized
5-9 wks,
remitting by 4 mo
of age
Autosomal recessive, with possible incomplete
penetrance and 7% diseased with heterozygosity
No bias 24
Petit Basset Griffon
Vendeen
Most focal onset, some with secondary
generalization
Mean of 2.2 y Likely hereditary basis owing to clustering within
litters
No bias 47
Schipperke Partial and generalized Mean of 4.4 y Not determined Not reported 48
Standard Poodle Most partial onset with secondary
generalization
3 y Not determined No bias 38
Standard Poodle Most partial onset, with occasional
secondary generalization
Under 7.5 y Simple autosomal recessive, with complete or
nearly complete penetrance
No bias 49
Vizsla Partial and generalized 1-3 y Autosomal recessive, possibly polygenic No bias 50
n
Breeds listed are those described in the literature possessing a clinical picture consistent with PE. The most specific speculated or known mode of inheritance provided
by the reference publication is provided
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 51–58 53
Table 2). NCLs are PMEs resulting from lysosomal storage disor-
ders, characterized by accumulation of autofluorescent lysosomal
storage bodies in the cells of the nervous system. Generalized
epileptic seizures may occur in NCL disease progression, occasion-
ally only in the terminal phase, and they are not universally
reported in all affected breeds.
71
The first genetic mutations
underlying NCLs were described in English Setters,
57
which harbor
a missense mutation in CLN8, and Border Collies,
58
with a non-
sense mutation in CLN5. Next, a missense mutation in CTSD was
described in American Bulldogs with NCL.
59
Two separate NCL
mutations have been described in Dachshunds: first, a single
nucleotide deletion, which predicted a frameshift and premature
stop codon in canine TPP1,
60
and second, a single nucleotide
insertion in canine PPT1.
61
An adult-onset NCL observed in
the American Staffordshire terrier, has been shown to result from
a nonsynonymous substitution in ARSG.
62
Finally, the remaining
2 NCLs are described in the Australian shepherd, resulting from a
missense mutation in CLN6,
63
and the Tibetan Terrier, a conse-
quence of a single nucleotide deletion in the gene ATP13A2.
64,65
It
is important to note that both Australian shepherds and Border
Collies have these published PME-causing mutations and they also
experience PE as a separate phenomenon (Table 1).
Only 1 of the canine NCL genes (ARSG) has not yet been
described in any human NCLs, whereas the other 7 genes, all
associated with lysosomal function, are known human NCL genes.
Interestingly, although mutations in orthologous genes often
cause a similar clinical picture in humans and dogs, this is not
always the case. For example, the ATP13A2 mutation in Tibetan
terriers causes NCL in that breed and a mutation in the same gene
likewise causes an autosomal recessive NCL in humans.
72
How-
ever, other mutations in human ATP13A2 cause Kufor-Rakeb
syndrome, a neurodegenerative disorder described as a juvenile-
onset parkinsonism, which is not classified as an NCL. Comparing
the mutations in gene function underpinning the expression of
PMEs for the different species has enhanced knowledge pertaining
to neural development and neurodegeneration in mammals.
Testing for Known Epilepsy Genes
For the practitioner, it is important to know which breeds
experience primary or metabolic epilepsies and for which breeds
genetic testing is available. The existence of such genetic tests can
be used to aid diagnosis, develop prognosis, and inform therapies.
They can also be used for screening purposes to aid breeders
when making decisions on which dogs to mate. While some
breeders are quite knowledgeable about genetic testing, others
may request or require assistance from their veterinarian. A web
application was recently developed (http://research.vet.upenn.edu/
WSAVA-LabSearch) as part of the World Small Animal Veterinary
Association, which summarizes gene and chromosomal locations,
mutations, and primary research citations, along with laboratories
currently offering genetic testing for each disease.
73
All 10 of the
described epilepsy gene mutations are cataloged on this website,
which is searchable by breed, disease or genetic test, or genetic
testing laboratory. For PE in which genetic testing is unavailable,
counseling breeders on strategies to minimize the incidence of the
condition based upon published modes of inheritance is needed.
Approaches to Identifying Causal Mutations in PE
In pursuit of the genes causing canine PE, many and varied
investigations have been undertaken. These attempts have met
with mixed results; only the Lagotto Romagnolo study described
earlier has uncovered a single causative gene for which genetic
testing is available.
A common approach to characterize mutations causative in
disease expression is by using genes (candidate genes) known to
function in a pathway associated with the disease. Candidate
genes are selected owing to the gene's biological function or
because a known mutation in a gene is associated with a similar
disease syndrome in another species. Candidate gene studies for
epilepsy therefore examine associations between disease status
and prespecified genes of interest. The studies are typically case-
control studies, with the DNA sequence of the gene(s) of interest
assessed for differences between the 2 groups. A second approach
in the search for causal mutations relies upon genetic linkage.
Genetic linkage studies require samples from affected and unaf-
fected family members and take advantage of the tendency of
genes and genetic markers physically adjacent to one another on a
chromosome to be inherited together during meiosis. Linkage
studies can be designed around candidate genes or can use DNA
Table 2
Identified Mutations in Canine Epilepsy
Breed Type Category Age of Onset Gene
Mutated
Type of Mutation Mode of
Inheritance
References
Lagotto Romagnolo Remitting PE 5-9 wks LGI2 Nonsense Autosomal
recessive
55
Miniature wirehaired
Dachshund
EPM2 (Lafora
disease)
PME 6-9 y EPM2B Dodecamer repeat
expansion
Autosomal
recessive
56
English Setter NCL PME 1-2 y CLN8 Missense Autosomal
recessive
57
Border Collie NCL PME Varies, but may be as early as
15 mo
CLN5 Nonsense Autosomal
recessive
58
American Bulldog NCL PME Before 2 y CTSD Missense Autosomal
recessive
59
Dachshund NCL PME At 9 mo TPP1 Single nucleotide deletion Autosomal
recessive
60
Dachshund NCL PME o9mo PPT1 Single nucleotide
insertion
Autosomal
recessive
61
American Staffordshire terrier NCL PME 3-5 y ARSG Nonsynonymous
substitution
Autosomal
recessive
62
Australian shepherd NCL PME o2y CLN6 Missense Autosomal
recessive
63
Tibetan Terrier NCL PME Adult onset ATP13A2 Single nucleotide deletion Autosomal
recessive
64,65
Breeds listed are those described in the literature with known genetic mutations causing their epilepsy and for which genetic tests are available.
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 51–5854
markers dispersed throughout the entire genome. Finally, GWA
studies use the dense, inherent variability (single nucleotide
polymorphisms [SNPs]) in the genome to compare the DNA of
cases and controls. The alleles defined by the SNPs or the genetic
markers are used to determine whether 1 allele occurs more often
in cases than in controls, thereby indicating the genetic region
associated with that allele is involved in disease expression.
One candidate gene study focused on genes already known to
be involved in human or murine genetic epilepsy.
74
The hypoth-
esis for the study was that a founder effect in the breeds would
enable linkage or association detection. Fifty-two genes, predom-
inantly for ion channels and neurotransmitter receptors, were
evaluated in Beagle, Greater Swiss Mountain Dog, English Springer
Spaniel, and Vizsla families. Despite the number of genes and dogs
assessed, no major associations or linkages to PE were uncovered
in any of the breeds and the plausible candidate genes were
essentially ruled out.
Although the Collie breed is not reported to have a high
prevalence of inherited PE, the well-known mutation in the ABCB1
gene (also known as the MDR1 or multidrug resistance 1 gene,
originally described in Collies sensitive to ivermectin
75
)was
recently investigated for an association with epilepsy in that
breed.
76
Of the 29 Collies with PE, 48% were homozygous for the
ABCB1 mutation, 38% were heterozygous for the mutation, and
only 14% were homozygous for the wild-type allele. Interestingly,
those homozygous for the mutation had significantly improved
seizure outcome (defined as having ≤1 seizure per month and no
cluster seizures while being maintained on at least 1 antiepileptic
drug [AED]) compared with the heterozygous dogs or dogs that
were homozygous for the wild-type allele. A similar study of
Australian shepherds
30
examined the ABCB1 mutation in 50 PE
cases and 50 controls and found that 22% of the cases and 18% of
the controls were heterozygous for the ABCB1 mutation, whereas
2% of both groups were homozygous for the mutation, indicating
no significant association between the mutation and PE. Further,
the ABCB1 genotype was unrelated to the age at the onset of
seizures, clinical course, remission, or seizure control with AEDs in
the Australian shepherd. The significance of these genotypic
findings as an aid in epilepsy prognosis, though intriguing,
remains uncertain; further investigations with additional Collies
and Australian shepherds, and inclusion of other breeds with the
ABCB1 mutation such as the Border Collie, are warranted.
Another candidate gene study examined a previously published
38-base pair variable number tandem repeat (VNTR) in the
dopamine transporter gene in epileptic Belgian Malinois.
77
The
VNTR is either present as a single copy or as 2 copies, with
the single copy being less common within the breed. Though the
number of PE-affected Belgian Malinois was small (n¼5), all
were homozygous for the single copy. In addition, Belgian Mali-
nois with at least 1 copy of the single VNTR had an increased
frequency of loss of responsiveness to environmental stimuli (such
as the dogs'eyes “glazing over”), which could be a clinical
manifestation of a focal seizure or an absence seizure. These
findings are preliminary and must be replicated in a large cohort
of dogs. The fact that a few dogs that were homozygous for the
single dopamine transporter VNTR did not have seizures implies
that this type of epilepsy in Belgian Malinois is likely caused by
more than 1 gene; indeed, a GWA study (described later) has
identified a second associated chromosomal locus.
The advent of high-density SNP arrays used in GWA studies are
valuable for complex trait assessment, although those conducted
for PE using the newer arrays in multiple breeds have met with
mixed success, underscoring once again the multifactorial nature
of the disease. Early linkage studies identified tentative loci
associations to several genomic regions associated with PE in the
Belgian Shepherd.
32
One of the loci identified was corroborated by
results obtained from a GWA study that identified in Belgian
Shepherd dogs a novel PE locus on Canis familiaris chromosome
(CFA) 37 (canine chromosome 37); the locus was confirmed in a
replication cohort.
78
A highly associated nonsynonymous CFA37
variant was identified in the ADAM23 gene, and homozygosity for
2 separate SNPs within this gene resulted in a high risk for
epilepsy. The gene product of ADAM23 interacts with proteins
LGI1 and LGI2, the latter of which has already been associated
with PE in Lagotto Romagnolos (described earlier). This locus may
also be associated with epilepsy in the Kromfohrländer and the
Whippet, although these breeds require confirmation in a larger
cohort. The variant, however, is not pathogenic based on predicted
changes to protein structure, therefore, this is not a causative
mutation. Further work, including targeted resequencing of the
locus, is being undertaken.
Other GWA studies of PE have identified suggestive loci. For
example, in Schipperkes, 2 loci were identified on CFA 26 and 31,
which were tentatively associated with PE.
48
The Australian
shepherd has likewise been studied in a GWA study, and associ-
ations were initially found to CFA19 (genome-wide significant)
and CFA1 (slightly less significant).
79
Replication cohorts ulti-
mately could not confirm the CFA19 association, but did improve
the CFA1 locus'significance slightly. Combined with the ABCB1
data mentioned earlier, these results suggest that PE in Australian
shepherds is genetically complex, with several loci involved in the
etiology. Other GWA studies have mapped PE loci to several
different chromosomes for various breeds, but specific mutations
have not yet been described.
80
Unfortunately, many GWA studies investigating canine PE
remain unpublished because results failed to achieve genome-
wide significance and do not identify any associated loci. This is
true for earlier genome-wide linkage studies and candidate gene
studies as well. Studies using fewer markers may have failed to
detect PE loci or all involved loci owing to lack of depth of
coverage. The fact that newer, high-density SNP arrays used in
recent studies also fail to uncover significant associations suggests
that many canine PEs are oligogenic or polygenic, not unlike what
has been observed in human PEs.
Pharmacogenetic Investigations of Canine PE
Parallel with the search for disease-causing epilepsy mutations,
studies have been undertaken to investigate the genetic response
to drugs and AED resistance in PE cases. For example, the ABCB1
gene (described earlier) has been examined in Border Collies with
PE. Affected Border Collies are often poorly controlled with AEDs,
and resistance develops in up to 71% of cases.
37
A recent study
determined that a sequence variation in the ABCB1 promoter
region (not the ivermectin sensitivity mutation found in exon 4)
was associated with drug responsiveness in this breed
81
; this may
indicate that expression of this gene could influence a dog's
reaction to AEDs. Another study examined Australian shepherds
with PE for the actual ivermectin sensitivity mutation (ABCB1
genotype) and seizure control, but they did not establish an
association.
30
Finally, a study examining the ABCB1 genotype in
Collies exhibiting PE observed that dogs homozygous for the
ABCB1 mutation received a reduced AED regimen than did
the other 2 genotypes
76
; specifically, the dogs homozygous for
the mutation, 93%, were given 1 AED, whereas the remaining 7%
received 2 AEDs; the dogs that were heterozygous for the
mutation or homozygous normal, were on 1 AED (40%), 2 AEDs
(53%), or 3 AEDs (1 dog). Doses of phenobarbital did not differ
significantly between genotypes; however, for those dogs receiv-
ing bromide, the dose was significantly lower in dogs homozygous
for the mutation compared with the other 2 genotypes. Similar
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 51–58 55
studies of epilepsy management in humans have yielded conflict-
ing results; a recent meta-analysis failed to identify an association
between ABCB1 genotype and response to AED treatment in
humans with epilepsy.
82
An earlier study pooled many breeds of epileptic dogs together
and used a custom SNP analysis of 30 genes involved in drug
metabolism, targeting, and transport to identify which, if any,
were associated with phenobarbital drug response.
83
A total of
5 genes were identified that were suggestive, although not
significant after adjustment for multiple comparisons, of associa-
tion with drug response. Not surprisingly, 2 were ion channels
genes (a potassium channel and a sodium channel) and 1 was a
gamma-aminobutyric acid neurotransmitter receptor gene.
Clearly, additional replication and breed-specific analyses are
required to further elucidate the role genetics plays in canine
response to AEDs, but initial work suggests that pharmacogenetic
drug responses in dog breeds is complex.
Nonepilepsy Seizure Disorders
Additional genetic diseases in dogs can result in seizures, yet
they would not be strictly classified as epilepsy. Although this
review does not aim to discuss such disorders exhaustively, a brief
description of 2 disorders is illustrative. For example, 2-hydroxy-
glutaric aciduria (2-HGA) is a group of metabolic disorders that
progressively damage brain tissue, resulting in a clinical presenta-
tion that resembles epilepsy, including seizures. Results of urinary
organic acid profile studies are also abnormal. L-2-HGA (with the
“L”indicating 1 of the 2 stereoisomers of hydroxyglutaric acid) has
been genetically described in both the Staffordshire Bull Terrier
84
and the Yorkshire Terrier.
85,86
Affected Staffordshire Bull Terriers
possess a 2-base pair substitution in exon 10 of the L2HGDH gene
that predicts a 2 amino acid substitution, whereas affected York-
shire Terriers have a single nucleotide substitution in the initiation
codon for methionine in their L2HGDH gene. Interestingly, the
phenotype of L-2-HGA in Yorkshire Terriers varies, with 1 study
showing an affected dog not presenting with seizures, but rather
episodes of hyperactivity and aggressive behavior. L-2-HGA has
also been observed in the West Highland White Terrrier,
87
although a molecular cause is not yet determined.
Though only described in a limited number of cases, another
example of nonepileptic seizures is startle disease in Irish Wolf-
hounds, which is inherited in an autosomal recessive manner.
Affected puppies developed tremors and muscle stiffness in
response to handling. During episodes, puppies are unable to
stand and have rigid extended posture of all limbs. A 4.2-kb
microdeletion was identified in the SLC6A5 gene, a presynaptic
glycine transporter.
88
Humans with startle disease develop similar
nonepileptic seizures.
Many other inherited neurologic conditions have also been
described in dogs; some now have known genetic mutations, but
for conciseness have not been discussed here. Genetic tests are
available for the 3 breeds with nonepilepsy seizure disorders descri-
bed above, and information regarding testing laboratories can be
accessed at http://research.vet.upenn.edu/WSAVA-LabSearch.
Concluding Remarks and Potential Directions
Significant work remains to be done in the field of inherited
canine epilepsies at all levels: diagnosis, testing, and therapeutic
intervention. The initial conjecture that PE in the different dog
breeds would be controlled by a single autosomal gene can no
longer be supported. The evidence is clear that canine PE is
polygenic with a large number of genes having a small effect each
on the expression of the condition. This is true for most human
genetic epilepsies and emphasizes the appropriateness of the
canine model of PE. Nevertheless, 10 genes are definitively
involved in canine epilepsies (1 for PE and 9 for PMEs), and these
have provided insight into neuronal function and development.
Many of the canine epilepsy genes are orthologous to those in
humans, therefore, although the expressed phenotypes can differ
between the species, canine epilepsy research has identified novel
genes for use in human studies and has deepened the knowledge
regarding neurotransmission and neurodevelopment.
Yet, success at identifying the genetic changes responsible for
inherited epilepsy is progressing slowly. The GWA studies are an
improvement over past research tools, but the multifaceted nature
of epilepsy requires creative combinations of genome sequencing
with metabolic profiles. An additional factor in complexity of the
study of epilepsy is that a single breed can express more than
1 form of genetic epilepsy.
55
In fact, for the Poodle, it has been
suggested that the genetics underlying PE could be different
between lines within a breed.
49
It is even possible that the
predisposition to epilepsy may be fixed in some breeds, and
expression of the disease is a result of modifying genes or
environmental influences, or both.
Analyses based upon DNA sequence mutations may fail to
identify structural variations such as copy number variants (CNVs)
or epigenetic modifications. CNVs are abundant throughout the
human genome
89,90
and human genetic epilepsies have been
associated with CNVs. In 1 study, nearly 9% of proband PE cases
were identified as having copy number changes.
91
CNV studies are
now being investigated in the dog.
92-94
Duplication variants
underlie the hair ridge in Rhodesian Ridgeback dogs
95
and familial
Shar-Pei fever,
96
and it is possible that similar kinds of mutations
are involved in PE for dogs. Microdeletions are shown to increase
the risk of idiopathic generalized epilepsy in some human
patients,
97-99
whereas certain large deletions (100 kb or larger)
create genetic risk for overall seizure susceptibility.
100
Employing
traditional GWA SNP studies combined with CNV analyses for
canine PE may prove more successful in situations where tradi-
tional GWA studies have failed.
Rapid-throughput whole-genome sequencing is becoming
much more common, and application of this technology on an
individual basis in dogs may help elucidate mutations, including
CNVs, which have been missed thus far. The use of whole-genome
sequencing in humans has identified a new epilepsy gene, a
sodium channel gene, not previously associated with epilepsy.
101
Epigenetics, the study of changes in gene expression not due to
direct alterations in sequence, including chromatin remodeling,
DNA methylation, histone modification, and noncoding RNAs, may
also play a role in PE susceptibility. In human epilepsies, epige-
netics is of increasing interest in teasing out disease susceptibility
and progression.
102
Epigenetic studies in dogs are in their infancy
and will undoubtedly move forward in the near future. Finally, the
idea of multihit models, well known in the context of cancer
genomics, implies that the presence of 1 mutation will not have a
major effect on pathogenesis in the absence of a second, or
numerous additional, mutations
103
; the complex genetic nature
seen in PEs suggests that multihit models may explain some of the
heritability of canine PEs.
In all the aforementioned study approaches, a key element that
requires resolution to advance progress in this area is definitive
classification and characterization of seizures. Difficulties sur-
round accurate phenotyping, a necessity in GWA studies, because
of the unpredictability of seizure occurrence and the reliance upon
owner-reported information. Subtle differences in seizure presen-
tation could very likely indicate different genetic causality. Human
epilepsy is categorized into more than 40 syndromes, classified by
age of onset, seizure stimuli, seizure characteristics, and EEG
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 51–5856
abnormalities. Practitioners can advocate for improved definition
of canine epileptic syndromes, and research directed at unifying
the diagnostic criteria would aid genetic researchers. Although it is
impractical for most canine PE patients to undergo EEG evaluation,
perhaps there exist metabolic markers that reflect a particular EEG
profile that could improve classification of the PE condition.
Similarly, it would be ideal for dogs classified as unaffected to
undergo EEG to verify normality before being included in genetic
studies as controls. One recent review
71
points out that there has
been a tendency to include reactive seizures in “case”groups of
dogs with PE, which may falsely inflate prevalence rates, and
would certainly affect the success of genetic investigations. For
example, Arrol et al.
104
recently examined 136 dogs whose first
seizure occurred before 1 year of age. Ultimately, 75% were
diagnosed with PE, while 17% were diagnosed with symptomatic
epilepsy, 7% with reactive, nonepileptic seizures, and 2 dogs were
considered probable symptomatic. This underscores the need for
specialized veterinarian diagnosis to prevent bias in classifying a
dog as having PE in juvenile-onset canine seizures.
Because inherited canine seizure disorders exist that cannot be
described as true epilepsy, it is essential for the practitioner to
consider the breed presenting with seizures and the patient's
clinical signs to discern how the seizure or seizurelike disorder
should be treated. This would guide decision making as to
whether or not genetic testing is appropriate, if the patient should
be treated with AEDs, or if other, or any, therapies will favorably
alter the course of disease.
The slow progress in identifying canine PE genes suggests that,
just as in humans and some mouse models, epilepsy may present
a much more complex genetic picture than originally hypothe-
sized. The data to date indicate that the genetic risk for epilepsy is
complex, including interaction between multiple genes and envi-
ronmental factors. Variants may contribute small effects, and
likely include both susceptibility and protective alleles. Canine
studies would move in the same direction as human studies, that
is, undertaking whole-genome sequencing of individual dogs,
combining CNV studies with existing GWA studies, and pursuing
epigenetic investigations. Though the remaining questions are
formidable, studies of genetic inherited epilepsy have not been
without reward. Ten gene tests are now available, and much work
is still in progress. The promise of identifying chromosomal loci
and genes involved in canine epilepsies brings hope for additional
susceptibility tests for dog breeders, increasing our knowledge of
the pathophysiology of neuronal hyperexcitation, and, possibly,
development of novel pharmaceutical or gene therapies or both.
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