Sleep Disorders in the family of Narcoleptics versus General Population

Narcolepsy is characterized by daytime sleep attacks and REM sleep abnormalities (cataplexy, sleep paralysis, hypnagogic hallucinations). Family history of narcolepsy has been reported in 6% to 40% of narcoleptic individuals (1-4). The risk for narcolepsy-cataplexy is estimated to be 10-40 times higher among the first-degree relatives of narcoleptic individuals than in the general population.

METHODS

The study was carried out by phone in the year 2000 using the Sleep-EVAL system (5,6).

PARTICIPANTS

Total Narcoleptics and their family N=433 subjects:

• 96 narcoleptic probands and
• their first-degree relatives (N=337; 86 fathers, 91 mothers, 69 brothers, and 91 sisters) aged between 13 and 91 years.

An environmental reference group of 85 subjects (aged between 13 and 66 years) including individuals living with a narcoleptic subject (spouse or roommate) or a close friend was also interviewed.

Participants from a representative sample of the general population of California and New York States (N=6,694) were used as a general population reference. The interviews were done in years 2003 and 2004 by telephone using the Sleep-EVAL system.

Four matching sets were constituted. Each of these groups matched by age, gender and Body Mass Index (BMI):

• fathers (n=400)
• mothers (n=685)
• brothers (n=509)
• sisters (n=543)

Total N=2,137 subjects.

VARIABLES

Information collected by the system included a description of narcolepsy symptoms: daytime sleepiness, cataplexy, hypnagogic and hypnopompic hallucinations, and sleep paralysis. Frequency, age of onset, time since the last episode were collected for each symptom. Information was also collected on sleep disorders diagnoses according to ICSD-97 classification.

The Sleep-EVAL system was previously validated on its ability to diagnose narcolepsy on its positive and differential diagnosis. The agreement between the Sleep-EVAL system and three sleep specialists was tested on 90 randomly selected participants. The Kappas between Sleep-EVAL and each sleep specialist were .89, .93, and 1.0.

DATA ANALYSES

Odds ratios were calculated with 95% CIs. Because in most cases CIs overlapped between the different groups of relatives, data are presented for all relatives but differences across relatives are noted when appropriate. Most comparisons were done using chi-squares with the Fisher's exact test for small groups.

RESULTS

Probands, brothers, sisters and environmental control subjects were comparable in age, education and occupation. Male probands were heavier than their brothers and environmental control group; 38.9% of them had a BMI >=30kg/m² compared to 13.0% in the brother group and 26.2% in the environmental control group. Female probands had a BMI comparable with those of other female groups.

CHARACTERISTICS OF NARCOLEPSY AMONG THE PROBANDS

Cataplexy was reported by 83.3%. HLA-DQB1*0602 was 79.1% positive (typing available for 67/96 probands). Cataplexy onset occurred during childhood (15.4%), adolescence (34.6%) or early adulthood (18-24 year old) (29.5%). Sleep paralysis (>=1 time/week) were reported by 37.5% of the probands. Only 13.5% said they never experienced it. Sleep paralysis began in childhood, adolescence or early adulthood in 8.3%, 27.7% and 44.5% of cases respectively. Hypnagogic hallucinations (>=1 time/week)> occurred in 49.0% and never in 18.8% of the cases. These hallucinations were qualified as frightening by 75.4%. Hallucinations first appeared during childhood, adolescence or early adulthood in that order: 22.2%, 29.8% and 27.0%. Automatic behaviors (>=1 time/week) were frequent (59.8%). Only 13.5% never experienced automatic behaviors. Difficulty initiating sleep (>=3 times/week) was reported by 9.4% of the probands; difficulty maintaining sleep (>=3 times/week)> by 71.9%; and non-restorative sleep by 61.5%. Subjects with narcolepsy had associated symptoms that occasionally met diagnostic criteria for additional ICSD diagnosis (Table 1). Probands had higher rates of confusional arousals, sleepwalking, sleep talking, nightmares, and REM behavior disorder four to six times higher than found in the corresponding environmental control group or the general population.

NARCOLEPSY IN FAMILY MEMBERS

Twenty probands out of 96 (20.8%) had at least one family member with narcolepsy. In 18 cases, only one other family member was affected with narcolepsy (2 fathers, 4 mothers, 7 sisters, and 5 brothers). Multiple cases of narcolepsy were found in the family of two male probands. Narcolepsy was confirmed for three fathers, five mothers, six sisters and one control subject during the clinical examination. A number of relatives larger than expected reported narcolepsy without cataplexy: 2.8% of all parents and 5.6% of brothers/sisters. An additional 1.7% of parents and 5% of brothers/sisters reported narcolepsy-cataplexy.

The relative risk for narcolepsy in relatives was 74.6 (OR: 17.5->100) when compared to the general population, as defined using the same diagnostic criteria and the Sleep-EVAL system.

SLEEP DISORDERS IN FAMILY MEMBERS

When compared to the general population, we found increased risk for multiple parasomnias and dyssomnias (tables 2 and 3).

None of the reported odd ratios differed significantly by sex but in 3 cases, they differed across generation (father/mother versus brother/sister). The most striking effects were a 6.1 fold increased in insufficient sleep syndrome and a 5.7 fold increase in nocturnal eating (drinking) syndrome.

DISCUSSION

We explored the prevalence of sleep disorders in first-degree relatives of subjects with narcolepsy. In this survey, the prevalence and risk for narcolepsy in relatives were slightly higher than previously reported figures (4-8). We found that 20 out of 96 probands (20.8%) had at least one first-degree relative with narcolepsy. Multiple cases of narcolepsy were found in two families. Risks for narcolepsy-cataplexy were 2.8-5.6% in first-degree relatives, a higher figure than the 1-2% previously reported risk. An additional 1.7-5% of relatives had narcolepsy without cataplexy. This figure for narcolepsy without cataplexy is consistent with other studies. Compared to the general population, the relative risk for narcolepsy was 74.6 in relatives. Several explanations support the higher prevalence of narcolepsy in our sample of relatives. Our proband sample included both narcolepsy with and without cataplexy cases in contrast with other studies. Cases without cataplexy or HLA-DQB1*0602 reported a positive family history more frequently. The increased prevalence in relatives may be due to the less strict definition of narcolepsy used in our telephone survey. A narcolepsy diagnosis in both our control population sample and the first-degree relative sample did not require verification using polysomnography. We found that many sleep disorder diagnoses were more frequent in narcoleptic patients' relatives when compared to the general population. This result is in agreement with another study (7) that found a 300 fold increased in risk for parasomnias in probands' relatives. Whereas the factors discussed above may be involved in some cases, substantial differences in relative risk across relatives were observed for selected disorders, suggesting additional effects. A human leukocyte antigen association for REM behavior disorder has been suggested, indicating possible shared genetic contribution. Other disorders with large increased risk in probands' relatives were nocturnal eating (with higher risk in brothers/sisters) insufficient sleep syndrome and adjustment sleep disorders. Whether these disorders confer some vulnerability to narcolepsy is unknown, but it should be noted that disruption in sleep wake patterns have been suggested to be frequent trigger for the development of narcolepsy. Similarly, hypocretin may regulate not only sleep but also metabolism and appetite, possibly explaining the association with nocturnal eating (8-10). This frequent association raises questions about the place of sleep-eating disorders inside of the parasomnia' spectrum and their links with narcolepsy.

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