ArticlePDF AvailableLiterature Review

Inherited Epilepsy in Dogs

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  • Purdue University College of Veterinary Medicine

Abstract and Figures

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.
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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 WisconsinRiver
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 dened 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 identied PE loci of interest; however, specic 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 reective of environmental interactions. An individual dog's response to therapeutic
intervention for epilepsy may also be genetically complex. Although the eld 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 classies human epilepsies and
denes 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 classica-
tion for epilepsy is a slight modication of that by the
International League Against Epilepsy: (1) primary/genetic epi-
lepsy (often termed idiopathicepilepsy), (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
classied as metabolic, despite the genetic cause of their disorder.
When chronic, recurring seizures occur and no underlying abnor-
mality is detected, the syndrome is classied 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 identied. 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 nonion 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 nonion 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) 5158
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 signicant 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 identication of novel genes involved in
central nervous system function. To some degree, this has proven
true as genes have now been identied for several reactive
(symptomatic metabolic) epilepsies and 1 PE in dogs. However,
canine epilepsy, similar to its human counterpart, remains plagued
with complex and difcult-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 briey, 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 uid 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
signicant 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 identied 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 sufcient information to denitively 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 classied 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 sufciently 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 GenesPE
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 stagespecic
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 rst 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 identied associations between PE and specic genes or
chromosomal loci, although none appears to be causative nor are
they available as genetic tests. The lack of denitively causal
mutations underscores the multifactorial nature of the condition;
this has been discussed in greater detail later.
Known Genetic Epilepsy GenesReactive 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
rst canine metabolic epilepsy mutation to be described was for
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 515852
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-
ed, 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 Inuence 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 Signicant 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 modied 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 specic 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) 5158 53
Table 2). NCLs are PMEs resulting from lysosomal storage disor-
ders, characterized by accumulation of autouorescent 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 rst 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: rst, 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 classied 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 prespecied 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
Identied 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) 515854
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 dened 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 signicantly improved
seizure outcome (dened 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 signicant 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 signicance of these genotypic
ndings 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
ndings 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
identied 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 identied tentative loci
associations to several genomic regions associated with PE in the
Belgian Shepherd.
32
One of the loci identied was corroborated by
results obtained from a GWA study that identied in Belgian
Shepherd dogs a novel PE locus on Canis familiaris chromosome
(CFA) 37 (canine chromosome 37); the locus was conrmed in a
replication cohort.
78
A highly associated nonsynonymous CFA37
variant was identied 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 conrmation 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 identied suggestive loci. For
example, in Schipperkes, 2 loci were identied 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 signicant)
and CFA1 (slightly less signicant).
79
Replication cohorts ulti-
mately could not conrm the CFA19 association, but did improve
the CFA1 locus'signicance 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 specic mutations
have not yet been described.
80
Unfortunately, many GWA studies investigating canine PE
remain unpublished because results failed to achieve genome-
wide signicance 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 signicant 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 inuence 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
; specically, 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
signicantly between genotypes; however, for those dogs receiv-
ing bromide, the dose was signicantly 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) 5158 55
studies of epilepsy management in humans have yielded conict-
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 identied that were suggestive, although not
signicant 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-specic 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 classied 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 prole studies are also abnormal. L-2-HGA (with the
Lindicating 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 identied 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
Signicant work remains to be done in the eld 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 denitively
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 identied 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 proles. 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 xed in some breeds, and
expression of the disease is a result of modifying genes or
environmental inuences, or both.
Analyses based upon DNA sequence mutations may fail to
identify structural variations such as copy number variants (CNVs)
or epigenetic modications. 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 identied 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 identied 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 modication, 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 denitive
classication and characterization of seizures. Difculties 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, classied by
age of onset, seizure stimuli, seizure characteristics, and EEG
K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 515856
abnormalities. Practitioners can advocate for improved denition
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 reect a particular EEG
prole that could improve classication of the PE condition.
Similarly, it would be ideal for dogs classied 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 casegroups of
dogs with PE, which may falsely inate prevalence rates, and
would certainly affect the success of genetic investigations. For
example, Arrol et al.
104
recently examined 136 dogs whose rst
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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K.J. Ekenstedt, A.M. Oberbauer / Topics in Companion An Med 28 (2013) 515858
... Idiopathic epilepsy, or repeated seizure activity with no clear etiology, has been observed across mixed and purebred dogs [1,2], although some breeds, such as Belgian shepherd, Irish Wolfhound, Labrador Retriever, Border Terrier, Petit Basset Griffon Vendén, Finnish Spitz, Italian Spinone, and German shepherd [3,4] exhibit a higher prevalence. Despite epilepsy being the most common neurological condition in dogs [5], and IE likely having the presence of genetic risk factors, there have been great challenges in identifying the genetic underpinnings of the disorder. ...
... Although there may be instances of specific seizure disorders presenting as a monogenic condition, at this time only in the Lagotto Romagnolo breed has a single gene (LGI2) influencing IE been identified [10] and a deletion in the DIRAS gene is associated with generalized juvenile myoclonic epilepsy in Rhodesian ridgeback dogs [11]. In contrast, many single genes have been identified as responsible for other forms of epilepsy such as the progressive myoclonic epilepsies in which a metabolic disturbance underlies the seizure episodes: NHLRC1/EPM2B for Lafora disease and CLN8, CLN5, CTSD, TPP1, PPT1, ARSG, CLN6, ATP13A2 for neuronal ceroid lipofuscinosis [2]. The prevalence of IE in the Belgian shepherd is a recognized health concern in the breed and breeders have sought means to reduce the incidence [12]. ...
... In the published literature for canine epilepsy, there are many identified genes that regulate myoclonic epilepsy [2], and focal seizures associated with fear or aggression have also been considered hereditary in certain dog breeds, with suspected risk variants uncovered [27,28]. Only for the Lagotto Romagnolo [10] and the Rhodesian ridgeback [11] has a single gene influencing IE been identified. ...
Article
Full-text available
Background Idiopathic epilepsy (IE) is a common neurological disorder in the domestic dog, and is defined as repeated seizure activity having no identifiable underlying cause. Some breeds, such as the Belgian shepherd dog, have a greater prevalence of the disorder. Previous studies in this and other breeds have identified ADAM23 as a gene that confers risk of IE, although additional loci are known to exist. The present study sought to identify additional loci that influence IE in the Belgian shepherd dog. Results Genome-wide association studies (GWAS) revealed a significant association between IE and CFA 14 ( p < 1.03 E − 08 ) and a suggestive association on CFA 37 ( p < 2.91 E − 06 ) in a region in linkage disequilibrium with ADAM23 . Logistic regression identified a 2-loci model that demonstrated interaction between the two chromosomal regions that when combined predicted IE risk with high sensitivity. Conclusions Two interacting loci, one each on CFAs 14 and 37, predictive of IE in the Belgian shepherd were identified. The loci are adjacent to potential candidate genes associated with neurological function. Further exploration of the region is warranted to identify causal variants underlying the association. Additionally, although the two loci were very good at predicting IE, they failed to capture all the risk, indicating additional loci or incomplete penetrance are also likely contributing to IE expression in the Belgian shepherd dog.
... Dog breeds, which have been identified as being predisposed to idiopathic epilepsy, include the Australian Shepherd, Belgian Tervueren, Belgian Shepherd, Border Collie, Irish Wolfhound, Labrador Retriever, Petit Basset Griffon Vendeen, Finnish Spitz Dog, and Italian Spinone (31,47). Even though pedigree analysis has strongly suggested genetic influence in these breeds, the identification of the affected genes has been quite difficult (47)(48)(49). Up to date, only a few monogenic epilepsies have been identified in dogs that parallel epilepsies in humans regarding epilepsy onset and seizure types (47). Thus, in contrast to the genetics of inherited human epilepsies, where modern techniques such as high-throughput sequencing have led to the identification of a progressively increasing high number of epilepsy syndromes, including the epileptic encephalopathies, with known genetic basis (36,42,45,(50)(51)(52), this area of research is in its infancy in canine epilepsy. ...
... In dogs, many studies of breeds with "idiopathic epilepsy" have failed to identify genes or loci of interest (47,49,251). Gene discovery in dogs with progressive myoclonic epilepsies (PMEs) has been more successful, with eight known genes; six of these are orthologous to corresponding human disorders (48,49). ...
... In dogs, many studies of breeds with "idiopathic epilepsy" have failed to identify genes or loci of interest (47,49,251). Gene discovery in dogs with progressive myoclonic epilepsies (PMEs) has been more successful, with eight known genes; six of these are orthologous to corresponding human disorders (48,49). In 2016, Hayward et al. (252) undertook the largest canine genomewide association study (GWAS) to date, with a panel of over 4,200 dogs genotyped at 180,000 markers, to accelerate mapping efforts. ...
Article
Full-text available
Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In both species, epilepsy is a complex brain disease characterized by an enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as in humans, status epilepticus is one of the more common neurological emergencies in dogs with epilepsy. In both species, 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. Brain imaging suggests that the limbic system, including the hippocampus and cingulate gyrus, is often affected in canine epilepsy, which could explain the high incidence of comorbid behavioral problems such as anxiety and cognitive alterations. Resistance to antiseizure medications is a significant problem in both canine and human epilepsy, so dogs can be used to study mechanisms of drug resistance and develop novel therapeutic strategies to benefit both species. Importantly, dogs are large enough to accommodate intracranial EEG and responsive neurostimulation devices designed for humans. Studies in epileptic dogs with such devices have reported ictal and interictal events that are remarkably similar to those occurring in human epilepsy. Continuous (24/7) EEG recordings in a select group of epileptic dogs for >1 year have provided a rich dataset of unprecedented length for studying seizure periodicities and developing new methods for seizure forecasting. The data presented in this review substantiate that canine epilepsy is an excellent translational model for several facets of epilepsy research. Furthermore, several techniques of inducing seizures in laboratory dogs are discussed as related to therapeutic advances. Importantly, the development of vagus nerve stimulation as a novel therapy for drug-resistant epilepsy in people was based on a series of studies in dogs with induced seizures. Dogs with naturally occurring or induced seizures provide excellent large-animal models to bridge the translational gap between rodents and humans in the development of novel therapies. Furthermore, because the dog is not only a preclinical species for human medicine but also a potential patient and pet, research on this species serves both veterinary and human medicine.
... Epilepsy, for example, is rather common among dogs (general prevalence is 0.5-5.7 %; see [92]), and certain breeds carry an increased risk of epilepsy with prevalence reaching up to 18% [93], indicating the presence of genetic risk factors. Yet, only a few associated polymorphisms have been described so far [94,95]. Studies that could directly investigate alterations in the transcriptomes and metabolomes of affected dogs' brains could be especially useful to pinpoint genetic causes. ...
Article
Full-text available
Biobanking refers to the systematic collection , storage, and distribution of pre-or post-mortem biological samples derived from volunteer donors. The demand for high-quality human specimens is clearly demonstrated by the number of newly emerging biobanking facilities and large international collabora-tive networks. Several animal species are relevant today in medical research; therefore, similar initiatives in comparative physiology could be fruitful. Dogs, in particular , are gaining increasing attention in translational research on complex phenomena, like aging, cancer, and neurodegenerative diseases. Therefore, biobanks gathering and storing dog biological materials together with related data could play a vital role in translational and veterinary research projects. To achieve these aims, a canine biobank should meet the same standards in sample quality and data management as human biobanks and should rely on well-designed collaborative networks between different professionals and dog owners. While efforts to create dog biobanks could face similar financial and technical challenges as their human counterparts , they can widen the spectrum of successful collaborative initiatives towards a better picture of dogs' physiology, disease, evolution, and translational potential. In this review, we provide an overview about the current state of dog biobanking and introduce the "Canine Brain and Tissue Bank" (CBTB)-a new, large-scale collaborative endeavor in the field.
... [52][53][54] In contrast, many studies of dog breeds with idiopathic epilepsies have failed to identify genes or loci of interest. 51 This slow progress suggests that IE in dogs, as seen in human epilepsies, is likely an extremely complex genetic picture, which is almost certainly polygenic with potential gene-environmental interactions. Although both challenging and expensive studies, successes in gene identification could give hope to dog breeders aiming to eradicate epilepsy in their breed, as has been attempted with some progressive myoclonic epilepsies, 52 Evidence for the efficacy of MCT supplementation to the diets of dogs with IE is increasing, with reductions in epileptic seizures, behavioral and cognitive comorbidities both when combined within a kibble diet [56][57][58] and when added as a supplement to a dog's base diet. ...
Article
Full-text available
Background: Epilepsy is the most common chronic neurological disease in dogs that adversely affects the quality of life (QoL) of affected dogs and their owners. Research on epilepsy in dogs is expanding internationally, but where best to focus limited research time, funds, and expertise to achieve better outcomes for affected dogs and their owners has not been studied. Objective: To explore idiopathic epilepsy (IE) research priorities of owners of dogs with IE, general practice veterinarians, and veterinary neurologists. Methods: An international online survey was conducted in 2016 and repeated in 2020. Participants rated the absolute importance and relative rank of 18 areas of IE research, which were compared between groups and time points. Results: Valid responses were received from 414 respondents in 2016 and 414 respondents in 2020. The development of new anti-seizure drugs (ASD) and improving the existing ASD management were considered the most important research priorities. Areas of research with increasing priority between 2016 and 2020 included non-ASD management, with the greatest potential seen in behavioral and dietary-based interventions. Disagreements in priorities were identified between groups; owners prioritized issues that impacted their and their dog's QoL, for example, adverse effects and comorbidities, whereas general practitioner vets and neurologists prioritized clinical issues and longer-term strategies to manage or prevent IE, respectively. Conclusions and clinical importance: Ensuring that voices of owners are heard in the planning of future research should be a broader goal of veterinary medicine, to target research efforts toward areas most likely to improve the QoL of the dog-owner dyad.
... In contrast to human epilepsy, EEG has not been routinely used in dogs, despite the fact that canine epilepsy is the most common neurological disturbance in veterinary medicine (26). In both cases described here, the dogs with LD presented EEG patterns similar to those described in humans, with solitary spikes or bursts occurring spontaneously or elicited by visual stimuli. ...
Article
Full-text available
Lafora Disease (LD) is a rare, fatal, late-onset, progressive form of myoclonic epilepsy, occurring in humans and dogs. Clinical manifestations of LD usually include seizures, spontaneous and reflex myoclonus with contractions of the neck and limb muscles. We studied the electroencephalogram (EEG) patterns of two beagles in whom LD was subsequently confirmed by genetic testing. In both cases, the EEG recordings, accompanied by electromyography (EMG), have shown similar uncommon patterns. The hypovoltaged background rhythm was interrupted by waxing “crescendo” polyspikes-slow wave complexes appearing 80–250 ms after the start of intermittent photic stimulation, followed by myoclonic jerks after 80–150 ms. This study highlights the value of EEG in establishing a presumptive diagnosis of LD in dogs.
... Idiopathic epilepsy (IE) is a common neurological disorder, with an estimated prevalence of 0.5% to 0.82% in the general canine population, and up to 33% in certain families of genetically predisposed breeds. [1][2][3][4][5][6][7] Drug resistance occurs in up to 30% of the dogs with IE leading to a grave prognosis and eventually euthanasia because of limited nonpharmacological treatment options. 8 Repetitive transcranial magnetic stimulation (rTMS) has received attention the recent years as a treatment method that can have neuromodulatory effects on the brain that last longer than the duration of the neurostimulation. ...
Article
Full-text available
Background: Although repetitive transcranial magnetic stimulation (rTMS) has been assessed in epileptic humans, clinical trials in epileptic dogs can provide additional insight. Objectives: Evaluate the potential antiepileptic effect of rTMS in dogs.Animals: Twelve client-owned dogs with drug-resistant idiopathic epilepsy (IE). Methods: Single-blinded randomized sham-controlled clinical trial (dogs allocated to active or sham rTMS) (I) and open-labelled uncontrolled clinical trial (dogs received active rTMS after sham rTMS) (II). Monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), and number of cluster seizures (CS) were evaluated for a3-month pre-TMS and post-rTMS period and safety was assessed. The lasting effectperiod of rTMS was assessed in each dog treated by active stimulation using theMSF ratio (proportion of post-TMS to pre-rTMS MSF) and treatment was considered effective if the ratio was <1. Results: No adverse effects were reported. In trial I, MSF and MSDF decreased significantly (P = .04) in the active group (n = 7). In the sham group (n = 5), no significant changes were found (P = .84 and .29, respectively). Cluster seizures did not change significantly in either group. No significant differences were detected between the groups. In trial II, previously sham-treated dogs (n = 5) received active rTMS and significant decreases in MSF and MSDF were noted (P = .03 and .008, respectively). The overall effect of rTMS lasted for 4 months; thereafter, the MSF ratio was >1. Conclusions and Clinical Importance: Repetitive transcranial magnetic stimulation may be a safe adjunctive treatment option for dogs with drug-resistant IE, but large-scale studies are needed to establish firm conclusions
... Idiopathic epilepsy (IE) is considered the most common chronic neurological disease in dogs, with an estimated prevalence varying from 0.5 to 5% in the general canine population (Podell et al., 1995;Ekenstedt and Oberbauer, 2013;Hülsmeyer et al., 2015). The treatment of canine IE is symptomatic and consists of the administration of anti-epileptic drugs (AEDs) aimed at decreasing the frequency and severity of the seizures . ...
Article
Epilepsy is the most common chronic neurological disorder in dogs. Approximately 20-30% of dogs do not achieve satisfactory seizure control with two or more anti-epileptic drugs at appropriate dosages. This condition, defined as refractory epilepsy, is a multifactorial condition involving both acquired and genetic factors. The P glycoprotein might play and important role in the pathophysiological mechanism and it is encoded by the ABCB1 gene. An association between a single nucleotide variation of the ABCB1 gene (c.-6-180T>G) and phenobarbital resistance has previously been reported in a Border collie population with idiopathic epilepsy. To date, the presence and relevance of this polymorphism has not been assessed in other breeds. A multicentre retrospective, case-control study was conducted to investigate associations between ABCB1 c.-6-180T>G, clinical variables, and refractoriness in a multi-breed population of dogs with refractory idiopathic epilepsy. A secondary aim was to evaluate the possible involvement of the ABCB1 c.-6-180T>G single nucleotide variation this population. Fifty-two refractory and 50 responsive dogs with idiopathic epilepsy were enrolled. Of these, 45 refractory and 50 responsive (control) dogs were genotyped. The G allele was found in several breeds, but there was no evidence of association with refractoriness (P=0.69). The uncertain role of the c.-6-180T>G variation was further suggested by an association between the T/T genotype with both refractoriness and responsiveness in different breeds. Furthermore, high seizure density (cluster seizure) was the main clinical risk factor for refractory idiopathic epilepsy (P=0.003).
Chapter
Machine learning is being used in the prediction of health and disease status in the animals and has wide scale application in the animal health care and well-being and veterinary sciences. In this chapter we have highlighted some of the applications of machine learning in the health and disease prediction in animals. Although the applications are at its infancy, the future scope of such application science in this domain of biology is immense and needs to be exploited more in the welfare of animal life.
Article
Full-text available
Epilepsy is a common neurological disorder that affects mammalian species including human beings and dogs. In order to discover novel drugs for the treatment of canine epilepsy, multiomics data were analyzed to identify epilepsy associated genes. In this research, the original ranking of associated genes was obtained by two high-throughput bioinformatics experiments: Genome Wide Association Study (GWAS) and microarray analysis. The association ranking of genes was enhanced by a re-ranking system, HPO-Shuffle, which integrated information from GWAS, microarray analysis and Human Phenotype Ontology database for further downstream analysis. After applying HPO-Shuffle, the association ranking of epilepsy genes were improved. Afterward, a weighted gene coexpression network analysis (WGCNA) led to a set of gene modules, which hinted a clear relevance between the high ranked genes and the target disease. Finally, WGCNA and connectivity map (CMap) analysis were performed on the integrated dataset to discover a potential drug list, in which a well-known anticonvulsant phensuximide was included.
Article
Full-text available
Lafora progressive myoclonus epilepsy is characterized by pathognomonic endoplasmic reticulum (ER)-associated polyglucosan accumulations. We previously discovered that mutations in EPM2A cause Lafora disease. Here, we identify a second gene associated with this disease, NHLRC1 (also called EPM2B), which encodes malin, a putative E3 ubiquitin ligase with a RING finger domain and six NHL motifs. Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy.
Article
Full-text available
Epilepsy afflicts 1% of humans and 5% of dogs. We report a canine epilepsy mutation and evidence for the existence of repeat-expansion disease outside humans. A canid-specific unstable dodecamer repeat in the Epm2b (Nhlrc1) gene recurrently expands, causing a fatal epilepsy and contributing to the high incidence of canine epilepsy. Tracing the repeat origins revealed two successive events, starting 50 million years ago, unique to canid evolution. A genetic test, presented here, will allow carrier and presymptomatic diagnosis and disease eradication. Clinicopathologic characterization establishes affected animals as a model for Lafora disease, the most severe teenage-onset human epilepsy.
Article
Full-text available
Background The Belgian Malinois dog breed (MAL) is frequently used in law enforcement and military environments. Owners have reported seizures and unpredictable behavioral changes including dogs’ eyes “glazing over,” dogs’ lack of response to environmental stimuli, and loss of behavioral inhibition including owner-directed biting behavior. Dogs with severe behavioral changes may be euthanized as they can represent a danger to humans and other dogs. In the dog, the dopamine transporter gene (DAT) contains a 38-base pair variable number tandem repeat (DAT-VNTR); alleles have either one or two copies of the 38-base pair sequence. The objective of this study was to assess frequency of DAT-VNTR alleles, and characterize the association between DAT-VNTR alleles and behavior in MAL and other breeds. Results In an American sample of 280 dogs comprising 26 breeds, most breeds are predominantly homozygous for the DAT-VNTR two-tandem-repeat allele (2/2). The one-tandem-repeat allele is over-represented in American MAL (AM-MAL) (n = 144), both as heterozygotes (1/2) and homozygotes (1/1). All AM-MAL with reported seizures (n = 5) were 1/1 genotype. For AM-MAL with at least one “1” allele (1/1 or 1/2 genotype, n = 121), owners reported higher levels of attention, increased frequency of episodic aggression, and increased frequency of loss of responsiveness to environmental stimuli. In behavior observations, Belgian Military Working Dogs (MWD) with 1/1 or 1/2 genotypes displayed fewer distracted behaviors and more stress-related behaviors such as lower posture and increased yawning. Handlers’ treatment of MWD varied with DAT-VNTR genotype as did dogs’ responses to handlers’ behavior. For 1/1 or 1/2 genotype MWD, 1) lower posture after the first aversive stimulus given by handlers was associated with poorer obedience performance; 2) increased aversive stimuli during protection exercises were associated with decreased performance; 3) more aversive stimuli during obedience were associated with more aversive stimuli during protection; and 4) handlers used more aversive stimuli in protection compared with obedience exercises. Conclusions The single copy allele of DAT-VNTR is associated with owner-reported seizures, loss of responsiveness to environmental stimuli, episodic aggression, and hyper-vigilance in MAL. Behavioral changes are associated with differential treatment by handlers. Findings should be considered preliminary until replicated in a larger sample.
Book
Handbook of Veterinary Neurology provides quick access to vital information on neurologic conditions in a wide range of species, including canine, feline, bovine, caprine, equine, ovine, and porcine. A problem-oriented approach makes it easy to diagnose and treat neurologic problems in small and large animals. The coverage of disorders by problem, not by established disease diagnosis, emulates how animals present to the veterinary hospital and simplifies the formulation of a correct diagnosis. Within each chapter, discussions of neurologic disease include a review of the localization criteria and the diseases that can cause that problem, plus treatment and surgical techniques. Lead author Michael D. Lorenz brings decades of experience to neurologic assessment, using a diagnostic approach that requires minimal knowledge of neuroanatomy. A problem-based approach is organized by presenting sign rather than by condition, guiding you to logical conclusions regarding diagnosis and treatment. Algorithms diagram the logic necessary to localize lesions and to formulate diagnostic plans. Coverage of current diagnostic techniques includes the use of diagnostic tools, such as radiology, spinal fluid analysis, electrodiagnosis, and MR imaging. Case histories in each chapter present a problem and the results of the neurologic examination, then ask you to solve the problem by localizing the lesion, listing probable causes, and making a diagnostic plan. Answers are provided at the back of the book. A consistent format for each case history includes signalment, history, physical examination findings, and neurologic examination. A comprehensive appendix describes species and breeds that have a congenital predisposition for particular neurologic diseases. Extensive references make it easy to pursue in-depth research of more advanced topics. A companion website includes 20 narrated video clips with accompanying PowerPoint slides that correlate to the case histories in the book, covering neurologic assessment and clinical problems such as paresis of one limb, tetraparesis, stupor, seizures, ataxia of the head and limbs, and cranial nerve disorders. Two new co-authors, Jean Coates and Marc Kent, board-certified in neurology, enhance the credibility of this edition. A full-color design and numerous illustrations include enhanced images of neuroanatomy and pathology.
Article
Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease.
Article
Neuronal ceroid lipofuscinosis (NCL) is a neurodegenerative disease found in Border collie dogs, humans, and other animals. Disease gene studies in humans and animals provided candidates for the NCL gene in Border collies. A combination of linkage analysis and comparative genomics localized the gene to CFA22 in an area syntenic to HSA13q that contains the CLN5 gene responsible for the Finnish variant of human late infantile NCL. Sequencing of CLN5 revealed a nonsense mutation (Q206X) within exon 4 that correlated with NCL in Border collies. This truncation mutation should result in a protein product of a size similar to that of some mutations identified in human CLN5 and therefore the Border collie may make a good model for human NCL. A simple test was developed to enable screening of the Border collie population for carriers so the disease can be eliminated as a problem in the breed. (c) 2005 Elsevier Inc. All rights reserved.
Article
Background Medically refractory seizures are an important problem in both humans and dogs with epilepsy. Altered expression of ABCB1, the gene encoding for p-glycoprotein (PGP), has been proposed to play a role in drug-resistant epilepsy. HypothesisHeterogeneity of the ABCB1 gene is associated with seizure outcome in dogs with epilepsy. AnimalsTwenty-nine Collies with epilepsy being treated with antiepileptic drugs (AEDs). Methods Prospective and retrospective cohort study. Dogs were classified as having a good outcome (≤1 seizure/month, no cluster seizures) or a poor outcome (>1 seizure/month, with or without cluster seizures) based on owner-completed questionnaire. Serum AED concentrations were measured, and ABCB1 genotyping was performed on buccal tissue samples. Association analyses were performed for genotype and seizure outcome, number of AEDs administered, serum AED concentrations, and incidence of adverse effects. ResultsFourteen dogs of 29 (48%) were homozygous for the ABCB1-1∆ mutation (M/M), 11 dogs (38%) were heterozygous (M/N), and 4 dogs (14%) had the wild-type genotype (N/N). Dogs with the M/M genotype were significantly more likely to have fewer seizures and have less AED-related sedation than M/N or N/N dogs (P = .003 and P = .001, respectively). Serum phenobarbital and bromide concentrations did not differ between groups, but the M/N and N/N groups received a larger number of AEDs than the M/M group (P = .014). Conclusions and Clinical ImportanceABCB1 genotype is associated with seizure outcome in Collies with epilepsy. This cannot be attributed to differences in PGP function, but might be because of intrinsic variations in seizure severity among phenotypes.
Article
Objective: To determine the proportion of mixed-breed and purebred dogs with common genetic disorders. Design: Case-control study. Animals: 27,254 dogs with an inherited disorder. Procedures: Electronic medical records were reviewed for 24 genetic disorders: hemangiosarcoma, lymphoma, mast cell tumor, osteosarcoma, aortic stenosis, dilated cardiomyopathy, hypertrophic cardiomyopathy, mitral valve dysplasia, patent ductus arteriosus, ventricular septal defect, hyperadrenocorticism, hypoadrenocorticism, hypothyroidism, elbow dysplasia, hip dysplasia, intervertebral disk disease, patellar luxation, ruptured cranial cruciate ligament, atopy or allergic dermatitis, bloat, cataracts, epilepsy, lens luxation, and portosystemic shunt. For each disorder, healthy controls matched for age, body weight, and sex to each affected dog were identified. Results: Genetic disorders differed in expression. No differences in expression of 13 genetic disorders were detected between purebred dogs and mixed-breed dogs (ie, hip dysplasia, hypo- and hyperadrenocorticism, cancers, lens luxation, and patellar luxation). Purebred dogs were more likely to have 10 genetic disorders, including dilated cardiomyopathy, elbow dysplasia, cataracts, and hypothyroidism. Mixed-breed dogs had a greater probability of ruptured cranial cruciate ligament. Conclusions and clinical relevance: Prevalence of genetic disorders in both populations was related to the specific disorder. Recently derived breeds or those from similar lineages appeared to be more susceptible to certain disorders that affect all closely related purebred dogs, whereas disorders with equal prevalence in the 2 populations suggested that those disorders represented more ancient mutations that are widely spread through the dog population. Results provided insight on how breeding practices may reduce prevalence of a disorder.