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HLA and genetic susceptibility to sleepwalking

Abstract

HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P=0.0056; odds ratio=3.5, 95% CI=1.4–8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission–disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P=0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep.

Main

Sleepwalking (SW) is a highly frequent sleep disorder of childhood affecting up to 20% of children.1 Although it has been proposed that SW generally disappears at adulthood,2,3 recent data in twins indicated that adult cases are found in a proportion of 1 to 3% and that most of them have suffered from SW since childhood.1 SW belongs to parasomnias and is explained as a disorder of arousal occurring during nonrapid eye movement (NREM) sleep.3 The condition is characterized by complex behaviors that are initiated during NREM sleep and result in walking during sleep with partial to complete amnesia the next day.4 Some authors have proposed a continuum with other NREM parasomnias such as sleep terrors or confusional awakenings.5,6 SW can seriously affect the life of a subject by its frequency (one or several episodes per night) or severity (risk of severe injury). Adolescents and adults with SW were found to have an increased prevalence of anxiety and personality disorders.7,8,9 Several cases of impulsion, aggression, and even homicide during SW episodes have been reported,10,11,12 indicating a potential danger associated with adult SW.

Epidemiological surveys including familial and twin studies have suggested a strong genetic implication in SW.6,13,14,15 Prevalence of SW in first-degree relatives of an affected subject has been estimated to be at least 10 times greater than that in the general population.6 Two modes of inheritance have been proposed, multifactorial6 and autosomal recessive with incomplete penetrance.2 However, based on the data reported here, an autosomal dominant mode of inheritance with variable penetrance cannot be excluded.

HLA-DQB antigens are known to be associated with disorders of rapid eye movement (REM) sleep, narcolepsy (DQB1*0602)16 and REM sleep behavior disorder (DQw1),17 both characterized by high parasomnia comorbidity.18,19 Therefore, we tested the hypothesis as to whether specific HLA-DQB1 subtypes may also contribute to genetic susceptibility to SW, the most prominent NREM sleep parasomnia.

Table 1 displays the sample characteristics. The overall age at onset of SW was 7.2 years (range 2–21 years). However, in Center 1 (child and adolescent psychiatry department), where 28 out of 29 subjects were under 18 years of age, the age at onset was significantly lower. In only seven cases, the onset occurred after the age of 10 years. A total of 25 patients (from 25 independent families) had at least one first-degree relative affected with SW and were considered as familial cases. One or several stressful triggering factors were reported by 34 subjects (56.7%), and included mainly family conflicts or job stress with a few cases of changes in sleeping environment, sleep deprivation, and alcohol. The frequency of SW episodes was from 1 per week up to several a night and therefore was considered moderate in 40 (weekly) and severe (nightly) in 20 cases. Anxiety was identified in one-third of the sample as the most frequent personality trait associated with SW. None of the subjects had a family history of epilepsy, and video-polysomnography in 29 subjects excluded any seizure-like activity. Motor manifestations (from clear out-of-bed walking in two cases to sitting up or leg and arm movements in nine cases) and abrupt arousals (lasting up to 2 min and associated with confusion, mumbling, or screaming) from sleep stages 3 and 4 were evidenced in 21 subjects (72.4%).

Table 1 Demographic, clinical, and polysomnographic data in SW patients

HLA-DQB1 allele distribution in sporadic, familial, and control subjects is shown in Table 2. No significant difference was found between sporadic and familial cases, and therefore the total SW population was compared to the control population. The DQB1*0501 frequency showed a significant increase in sleepwalkers (uncorrected P<0.006, corrected P<0.07, odds ratio=3.5, 95% CI=1.4–8.7) while DQB1*0602 tended to decrease (uncorrected P<0.1). Three (two sporadic and one familial) out of 21 DQB1*0501 positive patients were homozygous against none of the eight controls.

Table 2 Distribution of DQB1 alleles in SW and control subjects

The transmission/disequilibrium test (TDT) for DQB1*0501 in families indicated that 16 out of 23 heterozygous parents (69.6%) had transmitted this HLA allele to their affected child (TDT χ2=3.5, P=0.06). However, the excess transmission was only due to the familial cases since nine out of 11 DQB1*0501 heterozygous parents (81.8%) of familial cases had transmitted DQB1*0501 to their affected child (TDT χ2=4.45, P=0.035). The same analysis for other DQB1 alleles surprisingly revealed that the rare allele DQB1*0402 was six times transmitted against once non-transmitted (TDT χ2=3.57, P=0.06). This suggested that some DQB1 polymorphic amino acids might be more tightly associated than any single allele. Sequence analysis of all DQB1 alleles revealed that Ser74 in the second exon is shared between all DQB1*05 and DQB1*04 alleles. In the whole SW population, 36 (32.4%) were Ser74 against 16 (13.4%) in the control population (χ2=11.83, P=0.0006, odds ratio=3.1, 95% CI=1.6–6.0). The Ser74 phenotype distribution was not significantly different between familial and sporadic cases. Among sleepwalkers 27 (45.0%) were homozygous non-Ser74, 26 (43.3%) heterozygous Ser74, and 7 (11.7%) homozygous Ser74 vs 43 (71.7%), 16 (26.7%), and 1 (1.7%) in the control population (χ2=10.54, P=0.0051). Again, only in familial cases there was a strong excess transmission of Ser74 (20 times transmitted against 4 times non-transmitted, TDT χ2=10.67, P=0.001).

The frequency of Ser74 did not show any significant difference between age (positive in 48.2% of subjects age >18 years, n=27 vs 60.6% of subjects <18 years, n=33) or gender (positive in 50.0% of women, n=18 vs 59.5% of men, n=42). Only two out of seven subjects with the age at onset after 10 years were found to be Ser74 positive. Finally, clinical parameters (age at onset or severity) were not significantly different between DQB1*05 and/or Ser74 positive and negative patients.

These initial data in 60 subjects with SW disorder and their families indicate a positive association between the HLA-DQB1*05 subtype and SW. The frequency of DQB1*0501 was increased in SW patients while DQB1*0602 was slightly decreased. An opposite trend is found in narcolepsy where DQB1*0501 is protective.16 Detailed analysis in families indicates that the polymorphic amino acid Ser74 is the most tightly associated HLA-DQB1 polymorphism.

Our SW population may not be a representative sample of sleepwalkers in the general population for several reasons. The patients were not recruited from the general population but rather they were all referred to us with SW as their major complaint, indicating that SW was considered as a serious discomfort while most sleepwalkers probably never see a sleep specialist. This is also corroborated by the over-representation of adult (45%) and male cases (70%) in our sample. Nevertheless, several characteristics of our sample are also found in most previous studies. A recent epidemiological study20 indicated that the prevalence of SW was significantly lower after the age of 10 years, since in 77% of the cases SW was found to be present before the age of 10 years (88% in our sample). High anxiety and stressful triggering factors respectively observed in 30 and 56% of our patients are also found in several studies.20,21,22 Finally, although polysomnographically based diagnosis of SW is uneasy and can mainly be used for differential diagnosis of epileptic activity, complex motor manifestation and/or arousal from sleep stages 3 and 4 were evidened in 72% of our sleep recorded patients as also recently reported by others.23,24

Although our SW population came from three different countries (France, Germany, and Switzerland), population admixture may not be involved since the control population was matched for ethnic origin and the frequency of DQB1*05 in this population is similar to that found in other studies (25% in Caucasians). Also, the most convincing evidence is provided by a clear preferential transmission of Ser74 from heterozygous parents to affected subjects. Finally, since Ser74 is tightly associated with the familial form of SW, we believe that this HLA polymorphism might represent a major genetic susceptibility factor for SW. Nevertheless, the significant association found in this study may be due to linkage with other predisposing gene(s) in the HLA region. Therefore, further detailed HLA haplotyping (DQB1, DQA1, and DRB1) is warranted. Also, this first evidence for association in nuclear families needs further replication in extended SW families.

Our finding represents the first genetic marker for SW. DQB1*05 has also been implicated in REM sleep behavior disorder.17 A common genetic predisposition to SW and REM sleep behavior disorder may explain the coexistence of both disorders in some patients with the so-called parasomnia overlap disorder.19 Our findings suggest, as also hypothesized in other HLA-associated sleep disorders, a close relationship between the immune system and sleep. This relationship may involve some immune-related regulation of motor control during sleep.

Methods

All patients consulted one of the four collaborating sleep centers (Paris, France; Schwalmstadt-Treysa, Germany; Bern, Switzerland; and Montpellier, France) with SW as their major complaint. The study design was proposed to all sleepwalkers with well-established diagnosis and 60 consecutive Caucasian patients were included. Of 60 patients, 42 were men and 18 women, 33 children and adolescents (age range 5–18 years) and 27 adults (age range 18–67 years). In 25 cases, at least one other first-degree relative was affected and were considered as familial cases. At least one parent in 46 cases was available (23/25 in familial cases). Both parents were available in 33 cases (17 familial), in 11 cases only the mother (three familial), and in two cases only the father (both familial) was available. In addition, 10 siblings from five familial cases were also available. The diagnosis was based on clinical interview according to the international classification of sleep disorders,4 and if other sleep disorders or epilepsy was suspected subjects underwent polysomnographic evaluation (in 24/27 adult and 5/33 child+adolescent cases). The severity of SW was considered to be moderate to severe (frequent in children, up to once a week in adults; note also that all patients consulted on account of a serious complaint of SW).

Each participating sleep center was asked to recruit ethnically matched control subjects among relatives of patients with other unrelated and nonfamilial sleep disorders. The control group included 60 Caucasian subjects (27 men and 33 women) without any diagnosed sleep disorder. The experimental protocol was approved by each local ethical committee, and informed consent of each patient, family member, and control subject was obtained.

HLA-DQB1 gene polymorphism was resolved using a combination of group-specific amplifications and restriction fragment length polymorphism.25

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Acknowledgements

The Geneva University Hospitals supported this work.

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Correspondence to M Tafti.

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Lecendreux, M., Bassetti, C., Dauvilliers, Y. et al. HLA and genetic susceptibility to sleepwalking. Mol Psychiatry 8, 114–117 (2003). https://doi.org/10.1038/sj.mp.4001203

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Keywords

  • family-based association
  • transmission/disequilibrium test
  • amino acid polymorphism
  • anxiety
  • motor control

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