Margret L. Casal Dr med. vet, PhD, et.al.1, & Richard Munuve BVM1,
M. Anne Janis MS2, Petra Werner Dr med, vet1, & Paula Henthorn PhD1
From the 1Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania
and the 2Irish Wolfhound Seizure Study, Inc.
Acknowledgements: The authors thank the Jacky Karpinski fund
and the Irish Wolfhound Seizure Study fundraisers for financial assistance
and the owners and breeders for submitting the information needed for
this retrospective study. The Irish Wolfhound Seizure Study, Inc. is
a non-profit organization.
Abstract
During the last
fifteen years, an increase in the proportion of Irish Wolfhounds with
seizure disorders has been observed. Clinical data and pedigrees from
closely related Irish wolfhounds were collected retrospectively and analyzed.
Idiopathic epilepsy was diagnosed, by exclusion of other causes for seizures,
in 146 of 796 Irish wolfhounds (18.3%) from 115 litters. Males were more
commonly affected than females (61.6% versus 38.4%), and life expectancy
of affected dogs was decreased by two years when compared to the average
Irish wolfhound population. The heritability index for the affected dogs,
their littermates and unaffected parents was 0.87. The first seizure
occurred by age 3 years in 73% of all dogs and there appeared to be a
difference in the inheritance pattern between dogs with "early"
and "late" onset seizures. In the group with "early onset"
seizures, heritability increased slightly (0.88), and the gender bias
was no longer significant. An autosomal recessive mode of inheritance,
with incomplete penetrance and a possible sex-predilection, most simply
explains the segregation of epileptic dogs in the pedigrees examined.
Introduction
A seizure is defined
as "an occasional sudden, excessive, rapid, and local discharge of gray
matter" and may be generalized or partial (1).
Idiopathic epilepsy is the predominant diagnosis in dogs with generalized,
recurring seizures. Occasionally, some dogs with idiopathic epilepsy
may only experience focal seizures or may even retain consciousness during
the seizure. In the overall dog population 0.5 - 5.7% (2)
have seizures. Idiopathic epilepsy has been described in a variety of
dog breeds and has been suspected or shown to be a genetic disease (2).
Various modes of inheritance of epilepsy have been deduced in different
breeds, including simple autosomal recessive (3)
with a sex-modifier (4), (5),
polygenic recessive (6), with a sex-predilection
(7), polygenic with a large contribution by
a single autosomal recessive gene (8), and
a multi-locus model (9).
Over the years a
variety of medications have become available for the treatment of idiopathic
epilepsy in humans but only a handful have been tested and approved for
use in the dog (10). Unfortunately, therapy
is not always successful which often leads to euthanasia of affected
dogs (11). To reduce the number of losses,
the disease should be eliminated from the breed population, which can
be achieved with carefully designed breeding programs. However, in order
to develop such programs the mode of inheritance needs to be understood
and tests to determine carrier status must be developed. .
The purposes of
this study were to document idiopathic epilepsy and define the mode of
inheritance in the Irish wolfhound. Information on 146 affected and 1795
related, non-affected Irish wolfhounds collected by questionnaire and
pedigree analysis are presented here.
Materials
and Methods
Animals
Medical records
and pedigree information from 120 litters (N=706) of Irish wolfhounds
and their parents were obtained from veterinarians and owners by detailed
questionnaire including requests for relevant laboratory reports. The
diagnosis of idiopathic epilepsy in the 146 affected dogs was based on
a history of more than two seizures in the absence of other medical problems,
as defined by normal physical and neurological examinations, as well
as normal hematological, serum biochemical, and urine analyses. Additional
information collected included date of birth, gender, age of first observed
seizure, number of known seizures, age at death, and cause of death.
Owners of epileptic dogs also provided information on the seizure characteristics,
such as observation of partial or generalized motor problems, urination,
defecation, salivation, collapse and relationship of seizure onset to
the time of day, feeding, walking, sleeping or estrus cycle. Necropsies
were performed on 11 affected dogs at the Veterinary School of the University
of Pennsylvania, Department of Pathobiology and one at the Virginia-Maryland
Regional College of Veterinary Medicine, Department of Biomedical Sciences
and Pathobiology. Dogs were considered phenotypically unaffected if no
seizure had been observed during the dog's lifetime. Seizure-free dogs
that died before age four were not included in the data analysis and
37 dogs that had seizures in the presence of seizure-associated conditions
or diseases, such as hyperthermia, portosystemic shunts, head trauma,
or brain/neurological lesions, such as neoplasia and ehrlichiosis, were
excluded from the study.
Genetic analysis
Pedigrees were examined
from dogs with clear identifiers such as date of birth, age at death,
gender, and known health status of littermates. Dogs were considered
phenotypically unaffected if no seizure had been seen in absence of an
underlying brain/neurological lesion by four years of age or by the time
of their death. The vertical pedigrees were drawn and scrutinized to
see whether the phenotypes and the assumed genotypes in each generation
were compatible with expectations under assumptions of the simple Mendelian
modes of inheritance. Segregation analysis was performed to correct for
incomplete ascertainment (12) and the heritability
was calculated using standard methods (13)
Results
Clinical Findings
Idiopathic epilepsy
was diagnosed in 146 (18.3%) Irish wolfhounds from 120 related litters
containing 796 dogs. For females, the ages of their first observed seizure
ranged from 6 months to 84 months (mean=27.6±16.8). The incidence of
females with onset of seizures between 3 and 4 years of age was very
low, with the majority (82%) of first observed seizures occurring before
3 years of age (hereafter to be referred to as "early" onset seizures
versus "late" onset seizures beginning after age 3). The age of onset
for males ranged from 6 months to 107 months (mean=33.9±18.5; Figure
1). Only 67% of males experienced their first seizure before the age
of 3 years ("early onset"), whereas the onset of seizures occurred by
4 years of age in 83% of all male dogs. Overall, significantly more dogs
had their first seizure before 3 years of life than after three years
(p<0.05; Figure 1). In the 37-42 month and the 43-48 month age group,
significantly more males had their first seizure than did their female
counterparts (p<0.05).
Figure 1: Number of dogs at various ages at first seizure. Statistically significant differences in the age of onset of seizures (p<0.05) were seen between females from 37-48 months of age and the rest of the groups and between males and females for both the 37-42 month and the 43-48 month groups. Note the precipitous decrease in dogs with onset of seizure activity in the 37-42 month category followed by an increase.
The ratio of affected
male dogs (90) to female (56) was 1:0.62, differing significantly from
the 1:1.08 male to female ratio for the general Irish wolfhound population
during the same time period (p=0.001; an average of 2502 dogs were born
yearly). In the "early onset" group the ratio of affected males to females
(60:46) was not significantly different (p=0.27) from the general wolfhound
population. The coefficient of
inbreeding was calculated for 5 and 10 generations and was examined with
respect to the age of onset of disease in all dogs as well as in males
and females separately. There was no significant correlation between age
at first seizure and the coefficient of inbreeding, regardless of gender,
or in all dogs considered together (R2 = 0.02-0.06). However, in 23 litters
with multiple affected dogs, the onset of seizures in littermates occurred
within 12 months of each other with the exception of seven litters in which
one dog of each litter had its first seizure later in life. In the single
instance where affected full siblings were born in separate litters (2
affected dogs in each of two litters) , the age of first seizure covered
a range of 3 years (18, 31, 39, and 54 months,). The prodromal signs
observed by owners or breeders in affected dogs included: teeth chattering,
anxiety, mental detachment ("spaciness"), standing with a blank stare,
wandering aimlessly, increased attention seeking, and sitting or lying
down immediately before a seizure. Interestingly, some owners observed
"aberrant" behavior as puppies or months before the first seizure. Reported
aberrant behaviors included the dog submerging its entire head when drinking,
sound and touch sensitivity, shyness of doors or other barriers, exaggerated
flight distance, and shyness to an approaching perceived threat. Affected
males were often reported to be hyperactive and hard to control while females
were commonly reported as being withdrawn and unable to relax. The clinical signs
were generalized seizures, as defined by uncontrolled muscular activity.
All but four of the affected animals in this study experienced recurring
grand mal seizures, with seizure duration varying from 30 seconds to 4
minutes. Six of the affected dogs began with mild generalized seizures
that progressed to grand mal seizures over the course of their disease.
Two animals were reported as having petit mal seizures and another two
exhibited the "fly biting" type of seizure. In most dogs (38.4%) seizure
episodes occurred during sleep regardless of time of day. In other dogs
(13.7%), seizure episodes were reported to occur only while awake and active.
In 22.6% of the affected dogs, the seizures occurred both during sleep
and while awake. For 37 (25.3%) affected dogs this information was not
recorded by the owner. The duration of each seizure in a particular dog
was variable and was not predictive for the following seizure. Also, types
of seizures were variable within the litters with multiple affected dogs.
One affected dog had cluster seizures from the onset of disease, while
the condition advanced from single grand mal seizures to cluster seizures
in 29 affected Irish wolfhounds. While the "late onset" seizures were mainly
classified as grand mal type seizures, they subjectively appeared to be
milder and less frequent than seizures in the "early onset" dogs. In general,
cluster seizures did occur in the "late onset" population of dogs but they
were less common and the dogs required less medical treatment. Owners of
multiple seizuring dogs described the "late onset" seizure dogs as having
a better quality of life. The postictal phase
was characterized by wandering aimlessly, disorientation and confusion,
running into stationary objects, and increased hunger. Almost all of the
dogs with cluster seizures showed a prolonged recovery phase lasting more
than 36 hours. A change in general behavior was noted in 13 dogs after
the onset of disease. Recorded changes included sensitivity to noise (4
dogs) and light (1 dog), loss of vision (3 dogs), and shyness toward strangers
(5 dogs). There was no significant
difference in longevity after the first seizure between affected males
and females at p<0.05 (Figure 2). The average age of affected dogs
at death was 56.4 months. This is almost 2 years younger than the average
age of death within the general population of Irish wolfhounds of 6.5 years
of age 14. Of the 126 affected dogs that have died, 76 deaths (60.3%) were
directly attributed to the seizure disorder, with the cause of death reported
as death during seizure (16.1% of all seizure related deaths) or euthanasia
because of uncontrolled seizures (65.8%), hepatotoxicity from phenobarbital
treatment (6.6%), aspiration during seizures leading to fatal pneumonia
(6.6%), or euthanasia because of non-recovery after a seizure (3.9%). Fifty
affected dogs died of unrelated causes and 20 affected dogs were still
alive at the time of writing. Detailed necropsies were performed on 12
of the affected Irish wolfhounds that were included in the study. No neurological
or systemic lesions were found in these 12 dogs that could explain the
recurrent seizures. 
Figure 2: Life expectancy plotted against age at first seizure (± SEM). There was no statistically significant difference between any of the groups (p<0.05).
Drug Therapy
A relatively large
number of the affected dogs (36.6%) were not receiving any medication.
Conventional maintenance therapy of phenobarbital, potassium bromide, clorazepate,
dilantin or diazepam was used alone or in combination for the majority
of affected dogs. Phenobarbital was by far the most commonly used drug
for amelioration of the seizures, with 30.8% of all affected dogs receiving
this drug. In 13.7% of the animals, phenobarbital was used in combination
or alternately with potassium bromide. Potassium bromide alone was used
in only 4 dogs (2.7%). Gabapentins were used experimentally in 3 animals.
Two animals were treated with a combination of conventional and alternative
therapies. Four individuals were treated with homeopathic therapy alone.
None of the treatments eliminated the seizure activity but treatment was
reported by owners to reduce frequency and severity of the seizures in
the affected dogs. Interestingly, there was no discernable difference in
the frequency or severity of seizures with the use of homeopathy as compared
to conventional maintenance therapy. Side effects were reported from potassium
bromide (ataxia; 1 dog) and phenobarbital (hepatotoxicity and motor dysfunction;
5 dogs). Response to therapy within litters with multiple affected dogs
was not consistent, as each dog reacted differently to the same drugs given.
Genetic Analysis
Affected dogs were
present in 115 litters containing 773 dogs. Five litters (23 dogs) without
affected dogs were born to matings between parents that had both been known
to produce affected offspring. A representative portion of the larger pedigree
illustrating the inheritance of idiopathic epilepsy is shown in Figure
3. The average inbreeding coefficient (calculated over ten generations)
for all the dogs entered into the study was 0.156 with a range of 0.00353
- 0.35. The major observation made from examining the pedigree was that
the vast majority of affected dogs were born to healthy parents (143 affected
dogs from 112 litters). In keeping with this observation the trait was
observed to skip generations. In 37 of the litters born to unaffected parents,
one of the unaffected parents was related to other affected dogs. Only
3 of the affected dogs had an affected parent, and breedings between an
affected and an unaffected parent could produce either all unaffected offspring
or a mix of affected and unaffected offspring in the same litter. The segregation
ratio and the heritability (h2) were calculated from litters in which both
parents never had a history of seizures and in which medical information
was available on all littermates. Ascertainment bias was corrected for
using the singles method, as adopted by Nicholas 1987 13. The analysis
for all dogs resulted in an h2 of 0.87 and an estimated segregation ratio
of 0.083 ± 0.0001, which is significantly lower than would be expected
from a fully penetrant autosomal recessive trait. Because of the potential
difference between "early" and "late" onset seizures, the values were recalculated
using only affected dogs that had their first seizure before 36 months.
The h2 for the "early onset" group increased only slightly to 0.88 and
the estimated segregation ratio increased to 0.095 ± 0.0002. 
Figure 3: Small portion of the much larger pedigree of Irish wolfhounds with idiopathic epilepsy. Squares and circles represent males and females, respectively. Open and filled-in symbols designate normal dogs and affected wolfhounds, respectively. While not always indicated, all dogs in this pedigree have common ancestors.
Discussion
Idiopathic epilepsy
has been described in a variety of dog breeds along with different apparent
or suspected modes of inheritance. A familial predisposition had been recognized
early on in keeshonds, terriers, corgis, retrievers, pointers, setters,
spaniels, collies, Alsatian, boxers, Pekinese (15),
(16), Tervueren shepherd (17),
dachshund (15),(16),
(18), and in the Horak laboratory dog (19).
Since then, epilepsy has been the subject of investigation in many institutions.
In the German shepherd and in the keeshond, idiopathic epilepsy was thought
to have a simple autosomal recessive basis (3,)
(20-22). Epilepsy in beagles was thought to
be homologous to Lafora's disease in man based on the similar findings
from histopathological examination (23) and
the mode of inheritance was described as autosomal recessive with a sex-linked
"suppressor" (4), (5).
For epilepsy in the golden retriever, a multifactorial etiology, including
genetic and environmental factors has been described (9).
Larger studies were performed in the Labrador retriever, Bernese mountain
dog, and the Belgian tervueren. Pedigrees from 44 families with 55 epileptic
Labrador retrievers were analyzed and the results were suggestive of a
polygenic, recessive mode of inheritance (6).
Analysis of pedigrees from 4005 Bernese mountain dogs with 50 affected
dogs revealed a polygenic, recessive mode of inheritance with a predisposition
for males (7). The Tervueren has been described
as the dog breed with one of the highest incidences of seizures (17),
(24). It is, therefore, no surprise that a number
of genetic studies have been done in this breed, with results proposing
a single major gene with a large effect on seizures (8),
(24-26). This is the first report of hereditary
epilepsy in the Irish wolfhound breed. In our study, an 18.9%
incidence of idiopathic epilepsy was found among related Irish wolfhounds
with a high heritability of 0.91. These results suggest the presence of
a major gene, as the heritability was higher than 0.5. The heritability
did not change significantly if only dogs with "early onset" seizures were
used in the calculations suggesting that the "late onset" seizures also
have a genetic basis. In a similarly performed study a heritability of
0.77 was estimated in the Belgian Tervueren and 0.76 for the Belgian sheepdog
(8). In the Irish wolfhounds, significantly
more males were affected than females. This is in contrast to all but two
other studies in which no sex predilection was found (3),
(6), (8), (9).
The results in the Irish wolfhounds suggest the presence of a sex-modifier
gene, which is more similar to the findings in the beagle and the Bernese
mountain dog (4), (5),
(7). However, when only those dogs with onset
of seizure activity before 3 years of age were taken into account, there
was no significant difference between the percentage of affected females
and males. The age at first seizure
ranged from 6 months to almost nine years of age in the affected Irish
wolfhounds, with the majority (73.8%) of first seizures occurring at or
before three years of age. These results are similar to what has been found
in the general canine population (2), (27)
and in specific breeds (6),
(7), (9). In contrast, a study in Danish
Labrador retrievers s showed that the majority of seizures occurring before
4 years of age were only partial seizures and an equal number of generalized
seizures occurred before and after four years of age (28).
In beagles, the age of onset ranged from 11 to 70 months of age with 75%
of the seizures occurring before the age of 40 months, which is at a slightly
older age than in the Irish wolfhounds (4).
However, the number of beagles examined was much smaller than the Irish
wolfhounds in this study (29 versus 146). In the Irish wolfhounds, there
was no correlation between the type or onset of seizure and the coefficient
of inbreeding, similar to the findings in the Labrador and the Bernese
mountain dog (6), (7)Most of the Irish
wolfhounds had clinical signs and grand mal type seizures, consistent with
findings in almost all other studied dog breeds (2),
(4), (7), (9),
(27). However, grand mal seizures advanced to
cluster seizures in 29 (19.9%) of the affected Irish wolfhounds, which
is a large number considering that only 27% of all dogs referred for the
treatment of cluster seizures suffer from (primary) idiopathic epilepsy
(29). It is possible that the Irish wolfhounds
have a more severe form of idiopathic epilepsy than has been previously
reported in other breeds.Similar to affected
dogs of other breeds, none of the therapies eliminated the seizures completely,
but the frequency and severity of the clinical signs were reduced in most
Irish wolfhounds. Six dogs in the study exhibited side effects from their
therapy which resulted in death in five dogs; a finding which has been
described previously (30). Poor response to
treatment has been attributed to inadequate drug therapy (11),
(27), (29) and unresponsiveness
to therapy (8). Irish wolfhounds with
idiopathic epilepsy had a life expectancy that was decreased by two years
in comparison to the general Irish wolfhound population(14).
Of the affected dogs that died, 62% succumbed to disorders of quality of
life issues directly attributable to idiopathic epilepsy. These losses
and the decreased life expectancy underscore the need for elimination of
the disease from the breed by understanding the mode of inheritance so
that a breeding plan can be developed and possibly a genetic test for carrier
status. Pedigree examination
revealed several features supporting an autosomal recessive mode of inheritance.
A simple dominant mode of inheritance can be excluded because the vast
majority of affected dogs were born to clinically normal parents. An X-linked
mode of inheritance must be entertained because the incidence of seizures
in males was significantly higher than in females. However, almost all
of the affected females were born to clinically normal parents; in an X-linked
trait one would expect affected females to be born from affected males
bred to carrier females. The estimated segregation ratio is not consistent
with a fully penetrant simple autosomal recessive mode of inheritance.
It was therefore concluded that seizures in the Irish wolfhounds are inherited
as a non-fully penetrant autosomal recessive trait with a sex predilection
for males in all of the affected dogs and as a non-fully penetrant autosomal
recessive trait without a sex predilection in the "early onset" group.
Genetic studies in
humans and mice with idiopathic epilepsy have revealed a number of causative
genes for specific forms of epilepsy (31). Mutations
for monogenic epilepsies have been found primarily in genes coding for
ion channels (32) and also in two different
proteins that may be involved in neurogenesis (33).
More recently, the molecular basis for autosomal recessive progressive
myoclonic epilepsy (Lafora disease) in the miniature wirehaired dachshund
has been identified (34). However, this well-defined
form of epilepsy (not idiopathic) which is characterized by myoclonic type
seizures with rapid, progressive mental deterioration and polyglucosan
intracellular inclusions (35), is clearly distinct
from the form or forms of epilepsy observed in Irish Wolfhounds and other
breeds. In considering the genetic bases for epilepsy in various dog breeds,
including Irish wolfhounds it is important to consider that most forms
of idiopathic generalized epilepsy in humans are inherited as complex genetic
traits (36). A more recent study in humans has
demonstrated a major susceptibility gene with modifiers that influence
the clinical appearance of the seizure (37).
We suspect that a similar mechanism is responsible for the phenotypic appearance
of idiopathic epilepsy in the Irish wolfhound. Given the high heritability
of epilepsy in this breed, linkage analysis studies to determine the genes
involved are feasible. ConclusionThe high incidence
of seizures in the Irish wolfhound along with the decreased longevity in
affected animals and unsatisfactory treatment modalities underscore the
need for a breeding program designed to eliminate the disease from the
breed. Documentation of the inheritance pattern of the disease is important
not only in designing such a program, but also in performing additional
genetic studies that can lead to the development DNA-based genetic tests
for the identification of disease predisposing alleles, which can greatly
enhance the efficiency of such a program.
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Margret L. Casal Dr med. vet, PhD
E-mail: iwstudies@comcast.net
