Sleep. 1(4):413-422, 1979
© Raven Press, New York
Genetic Factors in Canine Narcolepsy
*Arthur S. Foutz, *Merrill M. Mitler,
tLuigi L. Cavalli-Sforza, and *William C. Dement
*Sleep Disorders Center and tDepartment of Genetics, Stanford
University School of Medicine, Stanford, California
Summary: The mating of narcoleptic Doberman pinschers yielded 30 puppies
in five litters, all of which developed the disease between 1 and 4 months of
age. Pedigrees of the Doberman probands are indicative of an autosomal recessive mode of transmission. An analysis of the pedigree of five affected Labrador retriever littermates suggests a similar mode of transmission. Crosses of
affected dogs in two other breeds (miniature poodles and beagles) have resulted
in all-unaffected F) generations, thus allowing rejection of the simplest genetic
hypothesis of a fully penetrant autosomal or sex-linked dominant or recessive
gene. Key Words: Narcolepsy-Heredity-Dog-Sleep-Animal modelCataplexy.
In humans, narcolepsy is a disabling, lifelong neurological disease characterized
by sudden attacks of complete, flaccid paralysis called cataplexy, continuous
sleepiness, sleep paralysis, and hypnagogic hallucinations (Guilleminault et aI.,
1976). Canine narcolepsy, which has recently been described (Knecht et aI., 1973;
Mitler et al., 1974; Darke and Jessen, 1977; Mitler and Dement, 1977), is a spontaneous animal model of the human syndrome (Mitler, 1976). This canine form of
the disorder, now known to affect at least 15 different breeds, has striking similarities to its human counterpart, including: (1) induction of cataplexy by excitement; (2) pathological manifestations of REM sleep, such as direct transitions
from wakefulness to REM sleep (sleep-onset REM sleep), and a near identity
between electro graphic manifestations of cataplexy and normal REM sleep (in
dogs), and either wakefulness or REM sleep (in man); (3) excessive daytime
sleepiness (Lucas et aI., 1978); (4) anticataplectic effects of imipramine and of
REM-suppressing drugs (Babcock et aI., 1976); and (5) early age of onset in dogs
and man.
One important aspect of human narcolepsy is its familial occurrence (Krabbe
Accepted for publication May 1979.
Dr. Mitler's present address is Department of Psychiatry and Behavioral Science, School of
Medicine, State University of New York at Stony Brook.
Address reprint requests to: Dr. Foutz at Sleep Laboratory, Stanford University School of
Medicine, Stanford, California 94305.
413
414
A. S. FOUTZ ET AL.
and Magnussen, 1942; Yoss and Daly, 1960; Nevsimalova-Bruhova and Roth,
1972; Kessler et aI., 1974; Baraitser and Parkes, 1978).
The possible involvement of genetic factors in canine narcolepsy was investigated by breeding affected dogs of three different breeds (Doberman pinschers,
beagles, and miniature poodles) and by collecting pedigrees of these and other
breeds of affected dogs in the Stanford colony. The breeding of affected Dobermans led to the development of a strain of dogs that seems to breed true for
narcolepsy and to the demonstration that genetic factors are involved in the etiology of narcolepsy. The pedigrees of affected Labradors also suggest a genetic
etiology.
MATERIAL AND METHODOLOGY
Material
Four narcoleptic Doberman pinschers were acquired after referral to us by
veterinarians; all four probands and their offsprings have been bred in our
facilities. The pedigrees of two of these Doberman probands were also available,
and their family history is reported. Four affected Labrador retriever puppies
from a single litter, with known pedigree, were also acquired. No history of
narcolepsy was reported for the four miniature poodles or for two beagles bred in
the colony.
Diagnosis of Narcolepsy
The clinical diagnosis of canine narcolepsy in the probands and their puppies is
based on the occurrence of cataplectic attacks. These attacks of flaccid paralysis
are elicited by the excitement associated with approaching desired goals such as
food, a play object or companion, and sexual activity. Two tests were devised to
assess the severity of cataplexy: the Food Elicited Cataplexy Test (FECT) and the
Play Elicited Cataplexy Test (PECT). For the FECT (Babcock et aI., 1976), ten 1
cm3 pieces of food are placed in a row, 30.5 cm apart; the time taken by the dog to
eat all ten pieces (elapsed time) is an index of the severity of cataplexy. For the
PECT, three to five dogs are placed together for 10 min in a large enclosure. The
number of complete or partial cataplectic attacks is recorded by the experimenter.
At an early age, PECTs are used satisfactorily, whereas the FECT is more efficient in adults.
Breeding Techniques
When estrus in the bitch is confirmed by a vaginal smear, she is bred on three or
four occasions, once every other day. When severe cataplectic attacks in the male
prevent complete coitus, the male can be assisted by the oral administration of 5
mg methylphenidate, which temporarily reduces cataplexy and has no deleterious
side effects on sexual function. When this procedure is not followed by a successful mating, the female is artificially inseminated.
Sleep. Vol. I, No.4, 1979
GENETIC FACTORS IN CANINE NARCOLEPSY
415
Environment
Adults and puppies are kept in standard outdoor-indoor kennels and exposed
only to the natural light-dark cycle.
RESULTS
Doberman-type Narcolepsy
The pedigree of the probands and their offspring are presented in Fig. 1.
Male 21 was donated by a veterinary school, and his pedigree is unknown. His
birthdate is approximately 1973.
Female 22 and her littermate sister (25) were born on June 26, 1975, from
unaffected parents. They both developed narcolepsy by 2 months of age. Two
other littermates (female 23 and male 24) developed the disease at the same age;
they were neutered and retained by the owner as pets. The four other dogs which
reached adulthood were unaffected. Two of them, male 26 and female 27, were
each bred once and reportedly had healthy litters. Both parents were also bred to
unrelated mates and, to the best of our knowledge, had normal litters. The dam
(12) yielded a completely normal litter of nine pups, and the sire (13) fathered
approximately 15 unaffected litters from different mates.
Female 39 was born on January 29, 1976, the offspring of an unaffected female
bred to her unaffected nephew. She had at least one affected littermate sister (40).
Two other littermates (one female, one male) were reportedly normal, but no
information could be obtained concerning the remaining five dogs.
A littermate sister (11) of the dam of probands 22 and 23 yielded four affected
males (16-19) in a litter of 10 when bred to her uncle. Two of these males,
severely affected, were terminated at 10 weeks of age, and the two others were
neutered after showing signs of narcolepsy at 6 weeks. One male died at 8 weeks,
apparently from erythrocytic hypoplasia. One male and four females are reportedly healthy.
Siblings born in the colony. The first litter of five pups was born on July 29,
1976, from probands 21 and 22. Two died of enteritis when 2 months old; the three
others (36- 38) survived and developed narcolepsy at 4 months of age. A second
litter of seven pups (29-35) was born from the same parents on December 3, 1976,
and all seven had cataplectic attacks between 4 and 5 weeks of age.
Proband 39 and FI male 38 yielded a litter of 10 pups on June 30, 1978. They
were all affected between 6 and 8 weeks of age. This cross was repeated, and all
eight surviving pups (five males, three females) in a litter of 12 born January 8,
1979, developed narcolepsy at a median age of 9 weeks.
Probands 21 and 25 yielded a litter of eight, of which six died from maternal
neglect. The two survivors had narcolepsy by 10 weeks of age.
In summary, three of our four probands (22, 25, and 39) can be traced to a
common ancestor (3), which IS also the progenitor of the partially affected litter
containing puppies 16-20. Three matings of related, healthy dogs yielded litters
with ratios of affected versus unaffected of 4/5, 4/4, and 2/2 (excluding the five
Sleep. Vol. 1. No.4. 1979
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FIG. 1. Pedigree of the Doberman pinscher colony. All offspring of the four probands (21, 22, 25, and 39)
were born in the Stanford colony. The most probable carriers beyond tHe immediate relatives of the probands
are indicated. Squares, males; circles, females; diamonds, either sex; black symbols, affected; open symbols,
unaffected; hatched symbols, status unknown; divided symbols, unaffected, presumed heterozygotes for the
autosomal recessive; small symbols, neonatal death. The number of individuals is indicated inside the larger
symbols. The arrows indicate the probands.
GENETIC FACTORS IN CANINE NARCOLEPSY
417
dogs of the last litter for which no information was available). These segregations
can be tested for their agreement with the 3: 1 ratio of normal to narcoleptic in a
cross between heterozygotes for a recessive in a simple although approximate
way, by omitting the three probands. This leaves a total of 11 unaffected to seven
affected, giving a X2 = 1.S5 with 1 d.f. (p > 5%). All breedings with unrelated
mates of those dogs who yielded partially affected litters when bred to related
mates resulted in all-unaffected litters. When both parents were affected, all 30
puppies of five litters were affected between 1 and 4 months of age.
Labrador-type Narcolepsy
Six cases of narcolepsy have recently appeared in two litters from related Labrador retrievers (Fig. 2). In one litter, born on May 12, 1978, five puppies out of
seven developed narcolepsy between 14 and 24 weeks of age; two others are
healthy at the time of this writing. Four of the affected puppies (15-1S) were
donated to the Stanford colony. A first litter of seven (three females, four males)
from the same parents, born in April 1976, was unaffected.
The sire (10) was also bred to a related female, which yielded a normal litter of
eight, and to 10 unrelated females, resulting in 66 healthy puppies.
The dam (9) was bred three times to two other dogs and had normal litters of
seven (four males, three females), eight (seven females, one male), and eight (four
males, four females) puppies. A cross between two offspring (12 and 13) of this
bitch and two different sires (S and 10) resulted in a litter of 11 survivors, now 2
years of age, of which only one female developed narcolepsy.
Poodle-type Narcolepsy
Three female and one male narcoleptic miniature poodles from the Stanford
colony, presumably unrelated, were bred and yielded 14 puppies in four litters
LABRADOR
RETRIEVER
FIG. 2. Pedigree of the Labrador retrievers. Same symbols as in Fig. J.
21
Sleep. Vol. I, No.4, 1979
418
A. S. FOUTZ ET AL.
MINIATURE
POODLES
20 21
L5
22 23 24
L4
FIG. 3. Pedigree of the miniature poodle colony. Birth date of each litter (month/day/year): Lt,
10/6/75; L2, 9/3/76; L3, 4112/77; L4, 3/23/78; L5, 4112/78. Male 13 died at 9 months of age, females 10
and 17 died at 21 and 15 months, respectively. Male 7 was born on 10/5/74 and terminated at 3 years II
months of age. Male 19 was born on 3/9/75. Crossed symbols, dead; thick symbols, alleged narcoleptic,
but diagnosis unconfirmed; other symbols same as in Fig. I.
(Fig. 3). The probands, male 3 and females 2, 4, and 5, had developed the disease
when 9 months, 4 months, 16 months, and 4 months old, respectively. Since an
additional male miniature poodle and a male miniature poodle-cocker mix were
affected at 2.5 and 4 months, respectively, 4 months was the median age of onset,
16 months the latest onset observed.
Of the 14 initial puppies, three died unaffected at 9, 15, and 21 months of age. Of
the 11 survivors, three (22-24) have not yet passed the age of risk (11 months old
on March 1, 1979), and the eight remaining are all still unaffected at the time ofthis
writing.
Two dogs born from a back-cross to female 2 have not passed the age of risk.
Beagle-type Narcolepsy
One severely affected male beagle (onset age, 4 to 5 months) and a mildly
affected female (narcoleptic at 2.5-3 years of age, cataplexy rarely experienced)
yielded seven puppies (five males, two females) born on April 18, 1978. All are
healthy at the present time.
DISCUSSION
There is still some disagreement as to the mode oftransmission of narcolepsy in
humans. Nevsimalova-Bruhova and Roth (1972), Kessler et al. (1974), and
Leckman and Gershon (1976) favor a multifactorial mode of inheritance. Baraitser
and Parkes (1978), while not excluding polygenic inheritance, suggest a single
dominant gene.
Narcolepsy is recessively inherited in the Doberman pedigree since (a) it appeared only when the dam and the sire were related, and (b) affected-to-affected
matings resulted in all-affected offspring. The high number of narcoleptic females
Sleep, Vol. I. No.4, 1979
GENETIC FACTORS IN CANINE NARCOLEPSY
419
born from unaffected parents rules out a sex-linkage. In the Labrador pedigree,
the birth of affected puppies of both sexes from related, unaffected parents
suggests a recessive autosomal mode of transmission. Crosses between affected
dogs will be made when sexual maturity is reached.
Since none of the FI poodle or beagle puppies has developed the disease,
narcolepsy in these breeds, if genetically transmitted, is likely to involve different
genes in the two mates. For the two puppies born from a back-cross, there is a
75% chance that at least one is homozygous for the dam's genes (since each pup in
such a back-cross has a 50% chance to be homozygous for the dam's homozygous
genes). They have not, however, passed the age of risk.
The other breeds represented in the Stanford colony have no documented cases
of narcolepsy among the littermates.
The heritability of narcolepsy does not appear to be linked to the severity of the
condition in the different breeds. The four poodle probands are all extremely
affected; they have literally hundreds of cataplectic attacks a day and require
300-900 sec to complete the FECT. Dobermans, in contrast, are much less severely affected. They have typical FECT values of 10 to 20 sec, with usually no
more than one or two incomplete cataplectic attacks (only the hindlimbs are
paralyzed for about a second). Labradors are even less affected than the Dobermans. For instance, two Labrador probands have only occasional cataplectic
attacks. Therefore, one cannot exclude the possibility of subthreshold abnormalities in Labradors that do not exhibit cataplexy. The abruptness of the cataplectic attacks, however, and their occurrence during periods of activity or excitement make even rare attacks easily noticeable.
Regardless of the differences in severity among breeds, all the narcoleptic dogs
of the Stanford colony have in common an early age of onset of cataplexy (62%
developed narcolepsy between 1 and 6 months of age and 82% before 2 years of
age) and a similar response to drugs: cataplexy is reduced by tricyclic antidepressants and REM sleep-suppressing drugs (Babcock et aI., 1976); the anticholinesterase physostigmine significantly increases the amount of cataplexy, whereas
anticholinergics such as atropine and scopolamine have anticataplectic properties
(Delashaw et aI., in press). Finally, analysis of the cisternal cerebrospinal fluid of
narcoleptic miniature poodles and of matched controls has revealed specific
neurochemical abnormalities. Affected poodles appear to have a decreased concentration and turnover of serotonin, a decreased concentration of dopamine, and
a decreased turnover of norepinephrine, as compared to normal controls of the
same breed (Faull et aI., in press).
Animal models have been described for several other heritable diseases affecting the nervous system, such as photosensitive epilepsy in Papio papio monkeys
(Naquet, 1975) or spinal muscular dystrophy in dogs (Sandefeldt et aI., 1976). Of
the numerous other inherited diseases of the nervous system, such as muscular
hypertonicity in dogs (Myers et aI., 1970) or brain diseases in mice, particularly
affecting the cerebellum (Sidman et aI., 1965; Sidman, 1976), few are considered
to be acceptable models for a specific human disorder. The mode of transmission
is generally considered different in the human disorder and its animal counterpart.
Narcolepsy in Dobermans and Labradors appears to follow this pattern.
Sleep, Vol. I, No.4, 1979
420
A. S. FOUTZ ET AL.
In summary, narcolepsy in Doberman pinschers and possibly in Labrador retrievers appears to be genetically transmitted by an autosomal recessive gene and
adds to the long list of inherited diseases in dogs (Fox, 1965). In miniature poodles, beagles, and other breeds data are only sufficient to exclude the simplest
genetic hypothesis of a fully penetrant autosomal or sex-linked dominant or recessive gene.
In addition, this study, by producing a strain of Doberman pinschers that breeds
true for narcolepsy, will permit extensive biochemical and pharmacological investigations with this animal model by providing a reliable source of atllicted
dogs.
ACKNOWLEDGMENT
This work was supported in part by National Institute of Neurological and
Communicative Disorders and Stroke grant NS 13211 and Research Scientist
Development Award MH 05804 (to W.C.D.).
The authors wish to thank the dog owners who donated their affected pets and
the clinicians who referred cases to us. We are particularly indebted to Drs. Pat
Baymiller, Byron Boysen, Joseph Carrillo, Alexander de Lahunta, Benjamin
Hart, Terrell Holliday, Richard Klein, Michael D. Lorenz, Larry Miller, Randy
Schuett, Stephen Seager, Anne Segedy, Steven Simpson, Michael Tierney, and
Donald Wood, and to Ms. Victoria Neyman, A. H. T., who successfully implemented the breeding program.
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