Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort.

OBJECTIVES: Sleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort. METHODS: Data from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22 years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N = 155 AA cases and 2598 AA controls; N = 512 EA cases and 4250 EA controls). RESULTS: Lifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth. CONCLUSION: The present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking.

Not Only Sleepwalking But NREM Parasomnia Irrespective of the Type Is Associated with HLA DQB1*05:01.

STUDY OBJECTIVES: Despite the high prevalence and clinical relevance of NREM parasomnias, data on supportive genetic markers are scarce, and mainly refer to sleepwalking only. METHODS: We retrospectively analyzed clinical, polysomnographic, and HLA findings of 74 adults (37 men) with NREM parasomnia gathered from four neurological sleep centers. Parasomniac events were classified according to ICSD-2 criteria. HLA DQB1 genotyping was compared to regional-matched reference allele-frequencies. RESULTS: Fifty-six patients had more than 2 different parasomnia type: 11 sleepwalking, 4 sleep terrors, 3 confusional arousals only. Parasomniac events were documented during video-polysomnography (V-PSG) in 70% (49/70) of subjects (71.4% confusional arousals, 8.2% sleep terrors, 4.1% sleepwalking, 16.3% ≥ 2 NREM parasomnia types). Violent behavior during V-PSG occurred in 8.5% (6/71). NREM parasomnia onset was reported after the age of 30 years in 6.8% (5/74). The HLA DQB1*05:01 allele was present in 41% (29/71) compared to 24.2% in the regional-matched reference allele group (p < 0.05). This haplotype prevalence did not differ within the NREM parasomnia type. Epworth Sleepiness Score was 10 or higher in 28.6%. CONCLUSIONS: This is a large polysomnography-based case series of patients with NREM parasomnia. In patients with suspected sleepwalking or sleep terrors, polysomnography is highly useful in detecting arousals from NREM sleep as a marker of NREM parasomnia. We confirmed previous findings by demonstrating a high prevalence of the HLA DQB1*05:01 genotype for different types of NREM parasomnias. Our findings therefore support a common genetic background, and corroborate the importance of video-polysomnography in the work-up of parasomnia.

Childhood Sleepwalking and Sleep Terrors: A Longitudinal Study of Prevalence and Familial Aggregation.

IMPORTANCE: Childhood sleepwalking and sleep terrors are 2 parasomnias with a risk of serious injury for which familial aggregation has been shown. OBJECTIVES: To assess the prevalence of sleepwalking and sleep terrors during childhood; to investigate the link between early sleep terrors and sleepwalking later in childhood; and to evaluate the degree of association between parental history of sleepwalking and presence of somnambulism and sleep terrors in children. DESIGN, SETTING, AND PARTICIPANTS: Sleep data from a large prospective longitudinal cohort (the Quebec Longitudinal Study of Child Development) of 1940 children born in 1997 and 1998 in the province were studied from March 1999 to March 2011. MAIN OUTCOMES AND MEASURES: Prevalence of sleep terrors and sleepwalking was assessed yearly from ages 1 1/2 and 2 1/2 years, respectively, to age 13 years through a questionnaire completed by the mother. Parental history of sleepwalking was also queried. RESULTS: The peak of prevalence was observed at 1 1/2 years for sleep terrors (34.4% of children; 95% CI, 32.3%-36.5%) and at age 10 years for sleepwalking (13.4%; 95% CI, 11.3%-15.5%). As many as one-third of the children who had early childhood sleep terrors developed sleepwalking later in childhood. The prevalence of childhood sleepwalking increases with the degree of parental history of sleepwalking: 22.5% (95% CI, 19.2%-25.8%) for children without a parental history of sleepwalking, 47.4% (95% CI, 38.9%-55.9%) for children who had 1 parent with a history of sleepwalking, and 61.5% (95% CI, 42.8%-80.2%) for children whose mother and father had a history of sleepwalking. Moreover, parental history of sleepwalking predicted the incidence of sleep terrors in children as well as the persistent nature of sleep terrors. CONCLUSIONS AND RELEVANCE: These findings substantiate the strong familial aggregation for the 2 parasomnias and lend support to the notion that sleepwalking and sleep terrors represent 2 manifestations of the same underlying pathophysiological entity.

Novel genetic findings in an extended family pedigree with sleepwalking.

BACKGROUND: Sleepwalking is a common and highly heritable sleep disorder. However, inheritance patterns of sleepwalking are poorly understood and there have been no prior reports of genes or chromosomal localization of genes responsible for this disorder. OBJECTIVE: To describe the inheritance pattern of sleepwalking in a 4-generation family and to identify the chromosomal location of a gene responsible for sleepwalking in this family. METHODS: Nine affected and 13 unaffected family members of a single large family were interviewed and DNA samples collected. Parametric linkage analysis was performed. RESULTS: Sleepwalking was inherited as an autosomal dominant disorder with reduced penetrance in this family. Genome-wide multipoint parametric linkage analysis for sleepwalking revealed a maximum logarithm of the odds score of 3.44 at chromosome 20q12-q13.12 between 55.6 and 61.4 cM. CONCLUSION: Sleepwalking may be transmitted as an autosomal dominant trait with reduced penetrance. Here we describe the first genetic locus for sleepwalking at chromosome 20q12-q13.12.

Sleepwalking, a possible side effect of antipsychotic medication.

Two case examples and a review of the sleep literature illustrate the potential of antipsychotic medication to trigger sleepwalking episodes in the context of schizophrenia. Causative hypotheses are briefly reviewed, as well as risk factors, differential diagnosis, and management. Sleepwalking may contribute to delusions, aggression, and accidental suicide. It is important to investigate sleep disorders in schizophrenia. They are not rare and may contribute to behavior that increases the stigma and isolation of individuals with schizophrenia.

Families with sleepwalking.

BACKGROUND: Studies on families with sleepwalking are uncommonly published but can give further information on the phenotype of patients with chronic sleepwalking. SUBJECTS AND METHODS: Out of 51 individuals referred for chronic sleepwalking during a 5-year period, we obtained sufficient information on 7 families with direct relatives who reported sleepwalking with or without sleep terrors. Among 70 living direct family members, we obtained questionnaire responses from 50 subjects and identified 34 cases with a history of sleepwalking. Of the 50 subjects, 16 completed only questionnaires, while all the others also completed a clinical evaluation and nocturnal sleep recordings. RESULTS: There was a positive history of sleepwalking on either the paternal or maternal side of the family over several generations in our 7 families. Thirty-three clinically evaluated subjects had evidence of sleep-disordered breathing (SDB), with associated craniofacial risk factors for SDB (particularly maxillary and/or mandibular deficiencies). There was a complete overlap with the report of parasomnias and the presence of SDB. In cases with current sleepwalking, treatment of SDB coincided with clear improvement of the parasomnia. CONCLUSION: All of our subjects with parasomnias presented with familial traits considered as risk factors for SDB. These anatomical risk factors are present at birth and even subtle SDB can lead to sleep disruption and instability of NREM sleep. The question raised is: are factors leading to chronic sleep disruption the familial traits responsible for familial sleepwalking?

Factors that predispose, prime and precipitate NREM parasomnias in adults: clinical and forensic implications.

Sleepwalking and related disorders are the result of factors that predispose, prime and precipitate episodes. In the absence of one or more of these factors sleepwalking is unlikely to occur. Predisposition to sleepwalking is based on genetic susceptibility and has a familial pattern. Priming factors include conditions and substances that increase slow wave sleep (SWS) or make arousal from sleep more difficult. These factors include sleep deprivation, alcohol, medications, situational stress and fever among others. The patient with a genetic predisposition to sleepwalking and with priming factors still requires a precipitating factor or trigger to set the sleepwalking episode in motion. Classical theories of sleepwalking were based primarily on case reports. Recently some of these theories have been tested in the sleep laboratory. Experimental sleep deprivation studies of sleepwalkers generally report an increase in complex behaviors during SWS, although one prominent study reported the opposite effect. However, the generally accepted theory that alcohol and medications can induce sleepwalking episodes remains entirely based on clinical and forensic case reports. Alleged cases of alcohol related sleepwalking often involve individuals lacking the generally accepted characteristics of sleepwalkers but with very high blood alcohol levels that could in and of itself account for complex behaviors noted without the presence of sleepwalking. Further, the effects of high levels of alcohol dramatically decrease SWS, a finding inconsistent with sleepwalking. Case reports of medication-related induction of apparent sleepwalking most often present a complex medical and psychiatric history associated with multiple medications. These patients often lack the clinical history and other criteria currently required for the diagnosis of sleepwalking. The medication-related behaviors may instead represent some other condition in an awake, but impaired patient. Sleep laboratory research has identified sleep disordered breathing, periodic leg movements, noise and touch among others as proximal triggers of sleepwalking episodes. Treatment of these triggers may result in resolution of sleepwalking without medication. Further sleep laboratory research is needed before experimental findings can be used for routine diagnostic and forensic purposes.

Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear.

Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.

[Somnambulism: clinical and eletrophysiological aspects]. / Az alvajárás klinikai es elektrofiziológiai jellemzói.

The authors review the literature on the epidemiology, the clinical and electrophysiological symptoms of somnambulism. The disorder specified as "nREM parasomnia with awakening disorder" belongs to the nREM sleep (awakening) parasomnias. In most of the cases its occurence is familial with the highest prevalence at age 12 year. Above age 12 year most cases recover whereas 6% of prevalence is reported in adults. It is probable that most patients seek medical help only in severe cases associated with injuries, accidents or violence. Its etiology is unknown; in essence it is a sleep regulation disorder characterised by a dissociated state of partial awakening from nREM sleep: the motor system becomes awake while consciousness remains clouded. There are several medicines inducing somnambulism in patients otherwise free from this disorder. In somnambule patients the most important provoking factors are sleep deprivation as well as pathological states and circumstances evoking sleep loss. Somnambulism should be differentiated from complex partial epileptic seizures and REM behaviour disorder. As there is no specific treatment at the moment it is important to assure safe sleeping circumstances - ground flour, closed windows, and no fragile furniture. Clonazepam and selective serotonin reuptake inhibitors prove sometimes effective, but the most effective methods in decreasing the frequency of somnambule episodes are the regular sleep-wakefulness schedule and the avoidance of sleep deprivation.

Sleepwalking violence: a sleep disorder, a legal dilemma, and a psychological challenge.

OBJECTIVE: The purpose of this article is to further an understanding of the psychological state when aggression follows an episode of partial arousal from early non-REM sleep during which some areas of the brain appear to be functioning as in waking while others appear to remain in a state of sleep. To illustrate this, the author examines a case of homicide for which the defense argued lack of responsibility due to sleepwalking. METHOD: A review of the forensic literature on sleepwalking aggression and sleep studies suggests that these fall into one or both of two DSM-IV-TR diagnoses: sleepwalking disorder and sleep terror disorder. The new case, which would meet criteria for an overlap disorder in which sleepwalking is followed by sleep terror, is compared to one previously published. RESULTS: These findings support sleepwalking violence as a distinct overlap disorder with common disturbed psychological functioning during and for a period up to 1 hour following an aggressive episode. CONCLUSIONS: Research clarifies the pathology of this disorder and highlights the need to both refine the differential diagnosis and test the efficacy of treatment protocols.

HLA and genetic susceptibility to sleepwalking.

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.

Parasomnias: co-occurrence and genetics.

In clinical practice, parasomnias are often found to run in families and to co-occur. Several studies have indicated a role of genetic factors in them. In 1990, a questionnaire (response rate, 77%) sent to the Finnish Twin Cohort, a representative population sample aged 33-60 years, surveyed the frequency of five parasomnias (sleepwalking, sleeptalking, enuresis, bruxism, and nightmares) in childhood and as adults. In assessing the phenotypic covariation and shared genetic effects between the parasomnias, we used polychoric correlations and structural equation modelling. In childhood (n = 5856 individuals), co-occurrence is highest in sleeptalking with sleepwalking (R = 0.73), nightmares (R = 0.50), and bruxism (R = 0.43). As adults (n = 8567), the results are similar (R = 0.56, 0.43, and 0.39, respectively). The analyses of shared genetic effects included 815 monozygotic and 1442 dizygotic twin pairs with complete responses on four parasomnias as adults. The strongest genetic covariation was found in sleeptalking with sleepwalking, sleeptalking with bruxism, and in sleeptalking with nightmares. The estimated proportions of shared genetic effects were 50, 30, and 26%, respectively. The present results indicate that parasomnias share some common genetic background.

Prevalence and genetics of sleepwalking: a population-based twin study.

We investigated the prevalence of sleepwalking using a well defined population previously used for epidemiologic investigations: the Finnish Twin Cohort. The study population consisted of 11,220 subjects aged 33 to 60 years, and it included 1,045 monozygotic and 1,899 dizygotic twin pairs. Questions on the frequency of sleepwalking were asked separately for occurrence in childhood and adulthood. Childhood sleepwalking was significantly more frequent in women ("often" in 2.8% of women and 2.0% of men and "sometimes" in 6.9% of women and 5.7% of men). As adults, sleepwalking had occurred in 3.9% of men and in 3.1% of women, and it was reported "weekly" in 0.4% for both genders. There was no significant difference in frequency between monozygotic and dizygotic twin individuals, either in childhood or adulthood. For sleepwalking in childhood the probandwise concordance rate was 0.55 for monozygotic and 0.35 for dizygotic pairs, and for adults, 0.32 for monozygotic, and 0.06 for dizygotic pairs. Those who reported never having walked in their sleep in childhood did so as adults rarely (0.6%), both men and women. Those who reported walking in their sleep often or sometimes in childhood did so as adults for 24.6% of men and for 18.3% of women. Of adult men sleepwalkers 88.9% had a positive history of sleepwalking in childhood, and in women, 84.5%. The proportion of total phenotypic variance attributed to genetic influences was 66% in men and 57% in women in childhood sleepwalking, and 80% in men and 36% in women in adult sleepwalking. Our results show that there are substantial genetic effects in sleepwalking in both childhood and adulthood.

[Automatic actions with amnesia induced by taking hypnotic drugs. Association with personal and familial history of somnambulism and epilepsy]. / Activités automatiques avec amnésie induites par la prise de médicaments hypnotiques. Association à un passé personnel et familial de somnambulisme et d'épilepsie.

A family which combined sleep-walking drug-induced sleep-walking and epilepsy is reported. This co-morbidity suggest various mechanisms which could explain drug induced sleep-walking. We stated the hypothesis that these behaviors were epileptic states due to a mini-withdrawal syndrome. This mini-withdrawal including of course a rebound of anxiety and insomnia during the day, but also a pro-convulsivant effect.

[Neurotic states in children with epileptic parents]. / Nevroticheskie sostoianiia u detei, roditeli kotorykh stradaiut épilepsiei.

On the basis of neurological, encephalographic and clinico-anamnestic examinations of 106 children with a family history of epilepsy the authors have specified a group of children (n = 38) suffering from different neurotic disorders which included neurotic ticks, sleep disturbances, affective-shock reactions and signs of asthenization. The role of familial factors in the formation of neurotic states of children is emphasized. The authors consider the time during which the child was exposed to psychotraumatic circumstances and the relationship between the severity of epileptic process in parents and the development of neurotic disorders in their progeny. A conclusion has been made that the disease of the parents can exert both direct and indirect influence on the nervous system of the child, this leading to the development of different neurotic states. The prophylaxis of neurotic disturbances in children should include the creation of healthy psychic atmosphere in families where one of the parents suffers from epilepsy.