Sleepwalking and Genetics

Twin and family studies suggest that sleepwalking is highly heritable. Despite recent advances in the genetic basis of many sleep disorders, including narcolepsy, restless leg syndrome, and REM behavior disorder, very little is known about the genetic basis of sleepwalking. One study reported an association of sleepwalking with human leukocyte antigen (HLA) DQB1*0501, but no other susceptibility genes have been reported.

In order to identify genetic susceptibility factors for sleepwalking, a large 4-generation family was ascertained in which sleepwalking segregates as an autosomal dominant condition with reduced penetrance. Linkage analysis revealed a region of markers on chromosome 20 that were shared among all 9 affected individuals. This sleepwalking linkage region on chromosome 20 contains more than 28 genes, including adenosine deaminase. Next-generation sequencing methods are ideal methods for studying mendelian forms of sleep disorders when they occur in large families. Therefore, exome sequencing was performed on the proband from this family, revealing >300 novel and >200 rare (MAF<0.05) genetic variants. Additional sleepwalking families are being studied for replication, most of which demonstrate autosomal dominant inheritance with incomplete penetrance. Recommendations for future study include: (1) Establishing the genetic relationship between various parasomnias (2) Developing diagnostic criteria useful for genetic studies, and (3) Collecting large parasomnia patient DNA cohorts for future genome-wide association studies and sequencing studies.

Sleepwalking: sleep disorder or disorder of arousal?

Sleepwalking is a nonREM parasomnia characterized by motor behaviour that can range from sitting up in bed to walking and even to apparent frantic attempts to escape. Somnambulism occurs most often during the first third of the night out of stages 3 and 4 sleep and accompanied by mental disorientation and relative unresponsiveness to external stimuli.

This work will first summarize currents views on sleep walking physiopathology and will review evidence for alterations of sleep and arousal responses in sleepwalkers. The second part will report recent findings on sleepwalking phenomenology. Although sleepwalking is often characterized in terms of its automatic behaviors and retrograde amnesia, ongoing work into the phenomenology of somnambulism indicates that for complex ambulatory behavior, cognitive and affective dimensions can play an important role.

We present here clinical case reports, questionnaire data, and laboratory observations indicating that some somnambulistic behaviors are construed by patients as being motivated by an intrinsic sense of urgency or underlying reason that accounts for their actions during their episodes. Based on these observations the mental content reported by sleepwalkers is best conceptualized as a form of hallucinatory rather than a dreaming process. Although these findings should not be taken as indicating that patients’ mental content directly precipitates somnambulism in and of itself, such reports raise important questions as to the role that phenomenological contents play in how somnambulistic episodes are experienced and unfold.

Clinical aspects and pathogenesis of sleepwalking

Sleepwalking (SW) is an arousal parasomnia of non-rapid eye movement (NREM) sleep where movement behaviours usually confined to wakefulness are displayed during sleep. It occurs in 2-14% of children and 1.6-2.4% of adults. We may dissociate primary sleepwalking often associated with sleep terrors and confusional arousals, and secondary or comorbid sleepwalking due to drug (mainly Zolpidem and Lithium) or substance (Alcohol) or due to medical condition (Parkinson’ disease and psychiatric conditions) and sleep disorder conditions (including OSAS, UARS, PLMD and RLS- PLMS). Sleepwalking is the result of factors that predispose or precipitate the episodes. Pathophysiology is still unclear with an inability to sustain slow wave sleep being the most probable hypothesis that may be genetically determined. The presence of hypersynchronous slow delta has been regularly reported in sleepwalkers, but their significance is controversial. SW is a common and highly heritable sleep disorder with a familial component in up to 80% of cases. Twin studies reported higher concordance for SW in monozygotic than in dizygotic twins (50% against 10-15%). We have reported a significant excess transmission for HLA DQB1*05 and *04 alleles in familial cases of SW. A recent study described an autosomal dominant inheritance pattern of sleepwalking with reduced penetrance in a 4-generation family. Linkage analysis for sleepwalking showed the first genetic locus for sleepwalking at chromosome 20q12-q13.12 (maximum odds score of 3.44). A recent study also reported overlap between parasomnias and sleep-disordered breathing within similar families.SW may lead to serious injuries but other consequences need to be evaluated in term of daytime sleepiness, fatigue, depressive symptoms and quality of life. Management of SW required the treatment of the triggering factors (stress, use of alcohol or drugs, sleep deprivation or fever) that may result in resolution of sleepwalking without medication. If sleepwalking is causing significant distress in spite of safety measures, a medical treatment is indicated. No powered rigorous controlled trials exist for the treatment of sleepwalking, but case reports and clinical experience revealed good efficacy of clonazepam.

Sleep Driving: Sleepwalking Variant, Residual Drug Effect or Both?

“Sleep Driving” - most often associated with sedative/hypnotic drugs, zolpidem and zopiclone in particular - is most often classified as a variant of sleepwalking.

The FDA has issued warnings that zolpidem and other sedative hypnotics may result in bizarre sleep related behavior. However, there are relatively few cases of sleep driving that include any clinical history or description of other sleepwalking characteristics. Instead episodes often labeled “Sleep Driving” often appear more consistent with impaired driving due to misuse or abuse of sedative/hypnotic drugs and reported behaviors most consistent with drug related CNS depression.

Impaired drivers have been reported to have:

  1. blood levels of z-drugs that exceed therapeutic ranges
  2. failed to take the medication at the correct time or remain in bed for sufficient time and/or
  3. combined z-drugs with other CNS depressants and/or alcohol.

Consistent with CNS depression z-drug impaired drivers are reported by police to demonstrate behaviors consistent with CNS depression and not sleepwalking.

“Sleep Drivers” demonstrate cognitive function at low levels but with drivers able to understand and respond to questions. Sleep drivers are often severely physically impaired, unable to stand up or maintain balance. Sleepwalker’s higher cognitive functions are generally absent. A sleepwalker would not be able to respond to police requests to produce driving documents or perform any sobriety tests. Additionally, they should have no problem standing or walking.

However “Sleep Driving’ episodes that occur with the patient taking a z-drug as prescribed, followed by a sudden arousal from sleep and complex behaviors such as driving may be a variant of sleepwalking at least in the beginning and middle of the episode. However, when the episode ends minutes later, significant blood levels of zolpidem or other sedative hypnotics may continue to be present resulting CNS depression.

Sleepwalking and residual drug effects after an awakening may overlap and be required to account for the impaired driver’s behavior.