Canine model of narcolepsy: Genetic and developmental determinants

EXPERIMENTAL NEUROLOGY 75,729-742 (1982)

Canine Model of Narcolepsy: Genetic and Developmental Determinants

THEODORE L. BAKER, ARTHUR S. FOUTZ, VICTORIA MCNERNEY, MERRILL M. MITLER, AND WILLIAM C. DEMENT’

Sleep Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305

Received September 25, 1981

Genetic and developmental factors were investigated in 101 cases of canine nar- colcpsy-cataplexy syndrome. An experimental breeding program documented a probable autosomal recessive mode of inheritance in two dog breads, Doberman pinschers and Labrador retrievers, and in crosses between those breeds. Age of onset of cataplexy and severity of symptoms were remarkably similar in 73 subjects with the genetically transmitted form of narcolepey. Efforts to demonstrate genetic factors by breeding affected poodles and beagles were unsuccessful. Furthermore, a positive family history could not be documented in these animals or in narcoleptic dogs of 13 other breeds. Both age of onset and severity of symptoms were highly variable within this population. We suggest there may be multiple etiologies in

canine narcolepsy syndrome: (i) inheritance via a single autosomal recessive gene, which appears to be identical in at least two unrelated dog bre& (ii) nongenetic mechanisms which may include developmental or traumatic accidents. Preliiinary findings of parallel neurochemical stud& in narcoleptic dogs indicate distinct abnormalities in central neurotransmitter concentration and turnover. We theorize that these neurochemical abnormalities may result from inherited disorders of syn- thesis and/or metabolism which are present from birth or from nongenetic neurochemical abnormalities appearing later in life. The observation that symptom characteristics are identical in all affected dogs suggests that a common neurochemical disorder may underlie both genetic and nongeneticvariations of the disease.

Abbreviations: FECT-food-elicited cataplexy test, MSLT-multiple sleep latency test. ’ We gratefully acknowledge the helpful suggestions of Dr. L. Cavalli-Sforza and Dr. J.-L.

Guerdoux. We also thank Cynthia Handen for assistance in animal care and breading. This research was supported in part by National Research Service Award, Postdoctoral Training Grant MH 15147-01 to Dr. Baker; National Institutes of Health Career Investigator Award MH 05804 to Dr. Dement; and Animal Resource Grant NS 15184. Dr. Foutz is currently Charge de Recherche au CNRS. The present address of Dr. Mitler is State University of New York at Stony Brook, NY 11790.

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INTRODUCTION

A century has passed since Gelineau (1880) described the narcolepsy syndrome in humans [for review see (9)], yet the etiology of this lifelong, disabling sleep disorder remains almost completely undefined. The recent discovery of an animal model of narcolepsy (13, 19) which presents re- markable similarities to its human counterpart (6, 20-22) has opened new opportunities for research. Since 1974, our group has acquired narcoleptic dogs of several breeds. An experimental breeding program led to the development of two strains of dog that breed true for narcolepsy and that now provide a steady supply of affected subjects for research purposes. We report here studies which demonstrate that canine narcolepsy is hereditarily transmitted by recessive genes in at least two breeds, Doberman pinschers and Labrador retrievers. Our results also suggest that in some cases of narcolepsy more complex multifactorial or entirely nongenetic processes may be involved in the etiology of the disease.

MATERIALS AND METHODOLOGY

Clinical observations were made on a total of 72 narcoleptic dogs. An additional 29 cases were reported to us by clinicians throughout the country.

Four narcoleptic Doberman pinschers, including two littermates, were acquired after referral to us by veterinarians; complete pedigrees were available for three of those dogs. All four probands and their offspring were bred in our facilities. In addition, a healthy Doberman male obtained through a pound and assumed to be a noncarrier for the trait was bred to the narcoleptic females.

Four affected Labrador retriever puppies from a single litter with known pedigree were acquired from their breeder. Narcoleptic Labrador retriever males were bred to their female littermates and to narcoleptic Doberman pinscher females.

No family history was reported for four narcoleptic miniature poodles or for two narcoleptic beagles that were acquired from various sources and experimentally bred within their respective breeds.

Diagnosis of Narcolepsy. The clinical diagnosis of narcolepsy in the probands and their puppies is primarily based on the occurence of attacks of flaccid paralysis (cataplexy) which appear spontaneously or are elicited by behavioral or pharmacologic provocative tests. Test procedures were detailed elsewhere (3, 6). Briefly, cataplectic attacks occur spontaneously in association with excitement of approaching desired goals such as food, a play object or companion, or sexual activity. A behavioral test based on this pattern is the food-elicited cataplexy test (FECT), which is routinely used to quantify the degree of cataplexy in the more severely affected

CANINE MODEL OF NARCOLEPSY 731

smaller breeds of dog (1). In the FECT test, 10 pieces of food are placed at equal distances in a row; the time required for the dog to eat all 10 pieces, including the interruptions caused by cataplectic attacks, is taken as an index of the severity of cataplexy.

A second method for assessing the severity of cataplexy is by direct behavioral observation of two to three dogs placed together for 15-30 min in a large enclosure. Cataplectic episodes are elicited by play behavior with toys or companions and by presentation of food. Number and duration of complete cataplectic attacks (affecting all postural muscles) and partial attacks (affecting usually the hind limbs) are recorded and timed by an observer assigned to each animal. Direct behavioral observation is more appropriate for testing young dogs or moderately affected adults, whereas the more regimented FECT is used for severely affected adult animals.

Provocative pharmacologic testing, used in conjunction with behavioral tests, consists of i.v. injection of an anticholinesterase (physostigmine) at doses from 0.025 to 0.1 mg/kg. This procedure dramatically increases the probability of spontaneous or elicited cataplectic attacks for 5 to 60 min after drug administration.

The age of onset of cataplexy in dogs whelped in our colony was determined by conducting 15 min of behavioral observation of each subject at least once per week beginning at 3 weeks of age. The age of onset in dogs which already displayed narcolepsy symptoms when acquired was esti- mated from medical records and by questioning breeders or owners.

Breeding Techniques. After determination of estrus by a vaginal smear, the bitch was bred on alternate days for 1 week. At times severe cataplectic attacks in the male or female prevented complete coitus, in which case 5 mg methylphenidate (Ritalin) was sometimes used effectively to tempo- rarily reduce cataplexy and facilitate the breeding. When this procedure failed to produce a successful mating, the female was artificially in- seminated.

Environment. Adults and puppies were kept in standard outdoor-indoor kennels and exposed only to the natural light-dark cycle. Some puppies whelped in the colony which had a low probability of developing narcolepsy were adopted as pets after they passed the age of maximum risk ( 10 weeks to 4 months) and failed to respond to provocative pharmacologic testing. The new owners were instructed to neuter or spay their pets at puberty. We thereafter regularly inquired about the health status of the dogs and reexamined and tested several of the dogs in our facilities.

RESULTS

Doberman Pinschers. The family history of probands 22, 25, and 39 (Fig. 1) was described elsewhere (5). Revealing patterns emerged from the

732

LABRADOR RETRIEVER

1 2

BAKER ET AL.

DOBERMAN PINSCHER

FIG. 1. Pedigree of the Doberman pinscher, Labrador retriever, and Doberman-Labrador mix colonies. All offspring of the probands (indicated by an arrow) were whelped in our facilities. A fourth litter from dogs 38 and 39 is not represented. The most probable carriers beyond the immediate relatives of the probands are indicated. Squares, males; circles, females; diamonds, either sex; solid symbols, affected; open symbols, unaffected; hatched symbols, status unknown; divided symbols, unaffected, presumed heterozygotes for the autosomal recessive; small symbols, neonatal death; cross symbols, deceased. The number of individuals is indicated inside the larger symbols. Birthdate of litters (month/day/year): Doberman pinschers, 1213 /77,6/29/78, 1/8/19,8/27/79,2/5/80,3/10/80,5/2/81; Labrador retriever, 5/14/81; Doberman-Labrador mix, 7/13/80, 5/11/81.

analysis of this pedigree. The breeding of healthy related subjects, such as female (No. 11) to her uncle (No. 7) female (No. 15) to her nephew (No. 28), or the more distantly related female No. 12 (littermate sister of female No. 11) to male No. 13, resulted in partially affected litters with ratios of affected:unaffected of 4:5, 2:2 (excluding five dogs for which no information was available), and 4:4, respectively. The outbreeding of these same dogs with unrelated or distantly related mates resulted in all unaffected litters: female No. 12 was bred once and had nine healthy puppies and male No. 13 sired approximately 15 litters from different mates.

The breedings that took place in our facilities confirmed these trends. When both parents were narcoleptic, all 41 Doberman pinscher puppies (seven litters) whelped in our colony showed first symptoms of .cataplexy between 1 and 4 months of age. As a final test for recessiveness, we outbred the affected bitch No. 39 (which had been bred four times to affected sire No. 38 and had whelped 29 affected puppies in four litters) to a healthy sire, presumably a noncarrier for the narcolepsy trait. All nine puppies from this cross were placed in private homes at 10 weeks of age after they failed to exhibit cataplexy during provocative pharmacologic testing. Five of these dogs (two males, three females) were followed for 2 years and remained nonaffected throughout this period.


Labrador Retrievers. Six cases of narcolepsy were diagnosed in two litters from related labrador retrievers (Fig. 1, left side). Cataplexy was first noticed by the breeders or owners between 14 and 24 weeks of age. To our knowledge the nonaffected littermates remained asymptomatic beyond 3 years of age. Seven dogs which were whelped 2 years earlier from the same parents also remained unaffected. The sire (No. 10) was bred to a related female which had 8 healthy puppies, and to 10 unrelated females which had 66 healthy puppies. The dam (No. 9) was bred three times to 2 other dogs and had 24 normal puppies in three litters. A cross between two offspring (Nos. 12 and 13) of this bitch which were sired by two different male dogs (Nos. 8 and 10) yielded a litter with 10 normal puppies and one narcoleptic female dog now 4 years old. In our colony, the breeding of littermates Nos. 15 and 18 yielded three male offspring; all had spontaneous cataplectic attacks by 9 weeks of age.

Doberman-Labrador Crosses. A female Doberman (No. 35) was bred to a male Labrador (No. 18), and 1 year later to the Labrador littermate brother (No. 17). Two litters were whelped, consisting of four and eight puppies, respectively. All dogs in the first litter (a-d) developed cataplexy by 10 weeks of age. In the second litter (e-l), provocative pharmacologic testing (0.10 mg/kg physostigmine) was carried out at 6 weeks of age, which elicited cataplexy in all puppies. Spontaneous cataplectic attacks first appeared between 8 and 10 weeks in this litter. Thus, cataplexy could be elicited pharmacologically 2 to 4 weeks before spontaneous cataplectic attacks were observed. This finding strongly suggests that the disorder is present in a covert form long before the first symptoms appear.

Miniature Poodles. Four probands, one male (No. 3) and three female (Nos. 2, 4, 5) narcoleptic miniature poodles, presumably unrelated, were bred in our facilities and yielded 14 puppies in four litters (Fig. 2). These probands had developed narcolepsy between 4 and 16 months of age (median age, 4 months), as detailed in Table 1.

Four of the initial 14 puppies bred in our facilities (Nos. 13, 17, 10, 16) died before 2 years of age (at 9, 15,2 1, and 22 months, respectively; crossed symbols on Fig. 2). Three dogs were lost or terminated between 2 and 3 years of age (Nos. 8,9, 18), four dogs between 3 and 4 years of age (Nos. 11, 12, 14, 15), and three have survived longer than 3.5 years (Nos. 19, 20, 21). Two dogs (Nos. 23,24) whelped from a back-cross of healthy sire (No. 8) to affected dam (No. 2), and two others (Nos. 26, 27) born from a back-cross of a healthy dam (No. 14) to affected sire (No. 3) remain healthy at 3.5 and 2.5 years of age, respectively.

In summary, none of the 10 surviving dogs of F, generation and none of the four dogs resulting from a back-cross of a healthy Fz offspring to a narcoleptic parent developed signs of narcolepsy. Furthermore, phar-

734 BAKER ET AL.

23 24

L5 25 26 27

L6

FIG. 2. Pedigree of the miniature poodle colony. Birth date of each litter (month/day/year): Ll, 10/6/75; L2, 9/3/76; L3,4/12/17; L4, 3/23/i%; 4/12/l& L6, 10/24/19. Crossed symbols, died before 2 years of age; thick symbols, alleged narcoleptic, but diagnosis unconfirmed; other symbols same as in Fig. 1.

macological testing with physostigmine failed to elicit cataplexy in any of the offspring of affected poodles.

Beagles. A severely affected male beagle (onset age, 4 to 5 months) and a mildly affected female beagle (narcoleptic at 2.5 to 3 years of age, cataplexy rarely experienced) yielded seven puppies (Fig. 3). Three male offspring (Nos. 6, 7, 8) were lost by their new owners at 10 months, 10 months, and 8 months, respectively; the others remained healthy beyond 1 year of age. Bitches 3 and 9 were retained and back-crossed to their affected sire (No. 2). Two of the resulting puppies (Nos. 18, 19) were lost or terminated at 4 and 8 months. Three other dogs died or were lost between 1 and 2 years of age. The remaining five dogs are unaffected at 2 years of age. The probability that none was homozygous for the sire’s homozygous genes is ( l/2)’ = 0.03 1. Pharmacological provocative tests were also unsuccessful in this breed.

Other Breeds. Narcolepsy was diagnosed in 13 other breeds and mixed breeds. In none of the 32 cases that we studied directly or that were reported to us was there evidence to suggest that littermates or relatives were affected.

Developmental Aspects. Cataplexy developed in most dogs at an early prepubertal age (Table 1). A detailed analysis reveals that in 52 Doberman pinschers, the earliest age of onset was 4 weeks, the median age 8 weeks, and the latest age 16 weeks. However, reports of the older ages of onset came from the first litter whelped in our facilities. It is likely that symptoms were inadvertently overlooked at an earlier age. Mean age of onset for the four most recent Doberman litters, which were observed at least twice weekly, was 7.5 weeks.

In Labrador retrievers and Labrador-doberman crosses, the onset of cataplexy followed a pattern similar to that in Dobermans; mean ages of


TABLE 1

Age of Onset of Cataplexy in 101 Cases of Canine Narcolepsy

Age of onset of cataplexy

Dog breed Inheritance Mean age at onset Median age Range (number of dogs tested) of disease f SD (weeks) (week-9 (weeks)

Doberman pinscher (52)

Labrador retriever (9)

Doberman-Labrador mixed breed (12)

Yes

YeS

Yes

Miniature poodle (7) No (?)

Beagle (3) No (?)

Daschund (4) Unknown

Miscellaneous breeds (14) Unknown Cockatoo (2) Chihuahua-terrier mix Irish setter (2) Wirehaired griffon Cocker spaniel Welsh corgi Springer spaniel St. Bernard (2) Afghan Airedale Malamute

8.6 * 2.1 8 4-16

14.4 + 5.6 14 8-24

9.2 + 0.9 9 8-10

Absolute ages of onset

10 weeks, 4 months; 4 months; 9 months; 16 months; 2 years; 6 years

38 lo-312

5 months; 4 months; 33 months

21 16-156

5 months; 7 months; 6 years; I years

30-312 21-364

4 month, 6 months 4 months 13 months; 6 months 7 weeks 12 weeks 3 years 6 years 2 years; 3 years 4 months I years 2 years

26 7-392

’ Seventy-three dogs inherited narcolepsy in experimental breedings within the Stanford Canine Narcolepsy colony. Those dogs had an early age of onset of cataplexy symptoms (mean 9.4 weeks). Twenty-eight dogs in 14 other breeds did not reproduce cataplexy symptoms in their offspring or had negative family histories. These dogs developed cataplexy at later ages (mean 124.8 weeks) and onset age was much more variable (10 weeks to 7 years).

onset for the Labrador and Labrador-Doberman mix offspring were 14 weeks and 9 weeks, respectively. By contrast, a wider dispersion existed for the other breeds in which genetic transmission of the disease was not

736 BAKER ET AL.

10 11 12 13 14 15 16

L2 L3

FIG. 3. Pedigree of the beagle colony. Birth date of each litter (month/day/year): Ll, 4/ 18/78, L2, 9/9/79; L3, 9/14/79. Crossed symbols, lost before 1 year of age; other symbols same as Fig. 1.

demonstrated: 10 weeks to 6 years in miniature poodles and 4 months to 3 years in beagles.

Doberman, Labrador, and Doberman-Labrador mix puppies abruptly developed symptoms. Several cataplectic attacks were usually observed during each behavioral testing session after the first cateplectic symptoms were noticed. As adults, these breeds show less severe cataplexy symptoms, as indicated by identical behavioral tests conducted after 1 year of age.

On the other hand, the breeds for which genetic transmission was not established tended to show a stable level of cataplexy throughout life when symptoms appeared. Two dogs acquired at an older age, a dachshund and a Chihuahua mixed breed, aged 2 years and 4 months, respectively, were reported to have attained a stable and permanent condition of cataplexy within a few days after first displaying symptoms. They were first examined in our facilities approximately 1 week after symptoms were noticed by their owners. Their condition has not changed significantly since that time, as revealed by numerous FECTs administered to gather baseline data in pharmacological studies. Similarly, poodles and beagles have shown little variation with time in FECT testing repeated during several years in some dogs. Medical records of other miscellaneous adult narcoleptic dogs also indicate an abrupt onset of cataplexy with little variation in symptom severity thereafter. These differences between breeds for which genetic transmission has been established and breeds for which there is little evidence for genetic factors further supports the hypothesis that there are at least two separate and distinct etiologies for canine narcolepsy.

Severity of Symptoms. The severity of symptoms was assessed in adult dogs by means of the FECT. There appeared to be a substantial difference


in severity among breeds. As adults, larger breeds were generally less affected than the smaller breeds (Table 2). Doberman pinschers rarely had FECT scores of more than 10 to 20 s, with one or two partial cataplectic attacks during the test. Labradors were even less acutely affected; they often had no attacks during FECT testing, but showed infrequent spontaneous attacks during play. The most severely affected dogs (miniature poodles, dachshunds) had hundreds of cataplectic attacks per day. Within any given breed, we could not define a relationship between the age of first

TABLE 2

Severity of Cataplexy Symptoms in 21 Adult Narcoleptic Dogs Assessed by Food-Elicited Cataplexy Tests (FECT)

Dog breed (number of animals tested)

Number Mean duration of tests of FECT (s) Range

Labrador retrievers (4)

Poodles (4)

Doberman pinschers (7) M 15 10f 5 6-26 M 7 11+ 4 7-18 M 12 43 f 63 S-238’ F 15 29 + 45 7-188’ F 15 14+ 10 7-47 F 16 9+ 6 5-28 F 6 13* 10 8-32

M 4 6+ 1 5-7 M 4 7+ 1 6-7 F 4 7+ 1 6-9 F 2 7+ 2 5-8

F 23 799 + 205 395-1319 F 68 749 f 196 312-1195 M 98 320 + 126 78-576 F 50 270 + 93 160-660

Other breeds (6) Beagle M Daschund M

F Wirehaired griffon M Chihuahua-terrier mix F Cockapoo M Australian-Shepherd mix F

89 185 + 78 6-597 145 689 f 176 260-1232

6 52 + 10 37-64 11 315 + 148 114-536 38 369 2 102 198-680 80 311 + 102 126-778 78 65 + 39 10-171

a Doberman and Labrador breeds, which inherit narcolepsy, had relatively mild symptoms as adults. They performed the test rapidly (mean 14.2 s) and rarely experienced complete cataplectic attacks during the FECT. We tested dogs of seven other breeds for which evidence of genetic transmission of narcolepsy was lacking. Those animals exhibited numerous complete attacks during FECTs and required much longer to complete the tests (average 384 s).

b Two Doberman pinschers had one complete cataplectic attack each during one FECT.

738 BAKER ET AL.

appearance and the severity of the symptoms. The most severely affected dog of our colony, a miniature poodle, developed narcolepsy at 16 months of age, whereas the median age for that breed was 4 to 9 months.

DISCUSSION

Our conclusion that narcolepsy is recessively and autosomally inherited in Doberman pinschers is based on the following observations: (a) narcolepsy symptoms appeared in offspring only when a nonaffected dam and sire were related, as revealed by the pedigree; (b) breedings between two affected parents resulted in all-affected offspring; (c) the mating of a narcoleptic bitch to a healthy sire presumed not to carry the trait resulted in an all-unaffected litter; (d) the large number of narcoleptic female dogs born from unaffected parents rules out heterosomal transmission.

The Labrador pedigree was also indicative of an autosomal mode of transmission. Furthermore, every offspring from the Doberman pinscher to Labrador retrievers breedings developed narcolepsy. This finding suggests that an identical gene was involved in the two breeds.

The pedigrees of beagles and miniature poodles did not suggest genetic transmission of the disease. Scattered reports of narcolepsy in other breeds also did not indicate a positive family history. Crosses between affected small and large breeds in our colony were not attempted.

Our results suggest that there may be at least two types of canine narcolepsy: (i) An inheritable form of narcolepsy has been described here, which appears in the first weeks of life and seems to be transmitted by an autosomal recessive gene. In this variation of the disease, symptoms are comparatively moderate in adult dogs (although extremely severe by the standards applied to human patients). (ii) A noninherited type of narcolepsy probably exists, which may be related to an accidental or developmental etiology. Symptoms in subjects with this latter type of narcolepsy are more heterogenous; the ages of onset vary from a few weeks to several years of age, and the severity of symptoms varies from extremely disabling to mild.

Another theory which can not be ruled out at this time is that more complex patterns of genetic transmission occur in some dog breeds. Thus, transmission by multiple genes or incomplete penetrance could account for the negative findings in some of these genetic experiments. However, this seems to be a remote possibility in view of the negative family history and total absence of affected offspring in these breeds.

It must be emphasized that although the severity of symptoms and age of their first appearance are extremely variable in the canine narcolepsy syndrome, possibly reflecting distinct etiologies as discussed above, the


clinical picture is remarkably similar in all subjects. Cataplectic attacks are always elicited by excitment, and are completely and instantly reversible (19). Symptoms are enhanced in all dogs by the administration of anti- cholinesterases (3). The electrophysiologic characteristics of cataplexy are in many cases indistinguishable from those of REM sleep in poodles or beagles (16), and Dobermans or Doberman-Labrador crosses (7).

Neurochemical Disorders in Narcolepsy. Neurochemical abnormalities were found in the cerebrospinal fluid of narcoleptic poodles versus normal controls of the same breed: a decreased concentration and a decreased turnover of serotonin, a decreased turnover of norepinephrine, and a decreased concentration of dopamine (4).

Recent studies in adult narcoleptic Dobermans, using a more sensitive technique of regional neurochemical analysis, demonstrated a general tendency toward decreased dopamine and serotonin utilization and turnover in many of the brain structures believed to be involved in the control of sleep-waking states ( 18). Studies in progress of regional brain neurochem- istry of Doberman pinscher puppies have yielded similar results. Thus it has become increasingly clear that distinct neurochemical abnormalities underly the canine narcolepsy syndrome both in Doberman pinschers and in poodles. In Doberman pinschers, it is likely that these neurochemical abnormalities are genetically determined. New evidence reported here that cataplexy can be elicited by pharmacologic provocation even before spontaneous symptoms appear suggests that these neurochemical abera- tions may be present from birth. In the apparently nongenetic cases of canine narcolepsy, factors such as central nervous system trauma, cere- brovascular accidents, or lesions could account for analagous neurochemical deficits.

Much further study is necessary to demonstrate that the neuorchemical abnormalities in narcoleptic dogs have a distinct causal relationship to narcolepsy symptoms. Pharmacological studies have provided evidence in support of this hypothesis. In general, drugs that inhibit cholinergic systems reduce cataplexy in dogs (a), whereas drugs that potentiate monoaminergic systems ameliorate symptoms (8).

Genetic Transmission in Human vs. Canine Narcolepsy. Of the several inheritable diseases affecting the neuromuscular system in dogs (26, 23) and other mammals (24, 28), 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. Her- itable canine narcolepsy appears to follow this pattern. Although there is still some disagreement as to the mode of transmission of narcolepsy in humans, most authors favor a multifactorial mode of inheritance (25, 12, 14). Other studies, although not excluding a polygenic mode of inheritance,

740 BAKER ET AL.

suggest a single dominant gene (2). Hereditary factors also appear to be involved in other sleep disorders, such as sleepwalking and night terrors (11). Finally, it is well known that in mice there is hereditary influence on sleep patterns and on the response to drugs which influence the aminergic mechanisms ( 17).

Cataplexy and Excessive Sleepiness. The first international symposium on narcolepsy (La Grande Motte, France, 1975) defined this syndrome by the occurrence of two symptoms which are necessary and sufficient for establishing a diagnosis: excessive somnolence and cataplexy (9). However, it is of interest to mention the very rare occurrence of patients with a seemingly hereditary form of cataplexy, but without associated signs of excessive’ sleepiness (29, 10). Unlike the common form of narcolepsy- cataplexy syndrome, which appears with a peak frequency during the pu- bertal years, “primary” cataplexy appears as early as the first months of life. Family histories suggest a dominant mode of transmission. Lack of sleepiness was documented with certainty in those patients (lo), using the Multiple Sleep Latency Test (MSLT), which is now routinely used to quantify sleep tendency in humans (27).

Whether excessive somnolence is present together with cataplexy in all affected dogs is as yet unresolved. Dogs sleep 54 to 57% of their lives (15, 20, 30) and their sleep-wake cycle is remarkably fragmented, which makes the quantification of their sleep tendency extremely difficult. However, a modified version of the human MSLT demonstrated an increased tendency to fall asleep in affected beagles and miniature poodles, versus healthy controls of the same breed ( 16).

In summary, it appears that distinct etiologies can determine canine narcolepsy: (i) an early onset, genetically transmitted type and (ii) a nongenetic or multifactorial type with possible developmental or accidental etiology, which is characterized by more variable age of onset. Because the symptoms appear to be identical in all affected animals and preliminary neurochemical findings are similar, the same final common pathway neurochemical or neuropathologic factors may underlie either type of canine narcolepsy.

SUMMARY

The breeding of narcoleptic dogs reveals that the narcoleptic syndrome is genetically transmitted in Doberman pinschers by an autosomal recessive mode. In Labrador retrievers, narcolepsy is also recessively inherited and appears to involve the same gene as in Dobermans.

Crosses of affected dogs in two other breeds (beagles and miniature poodles) have not yielded any affected offspring of the F, generation. The


F2 generation offspring (back-crosses of unaffected F, individuals to their affected parents) are also asymptomatic, which further supports the hypothesis of a nongenetic etiology in these breeds.

Comparisons of age of onset of cataplexy and severity of symptoms in different breeds suggests the existence of different narcolepsy populations, in agreement with the genetic studies. Inheritable narcolepsy in dogs is characterized by relatively mild symptoms in adulthood, which first appear at an early prepubescent age in a much more severe form. In a second population of narcoleptic animals, the disease apparently has a nongenetic or multifactorial etiology. In this group, symptoms often begin at a much later age and the severity of symptoms is highly variable.

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Canine model of narcolepsy: Genetic and developmental determinants