Familial sleep traits

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Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.

Circadian rhythms are coordinated physiological and biological changes that oscillate on an approximately 24-hour cycle. Disruptions to these rhythms in humans may affect the duration, onset, and/or quality of sleep during this cycle, resulting in familial sleep traits. These traits are not necessarily syndromes because they do not always cause distress among individuals. Instead of being disorders, familial sleep traits are variations in an individual's biological tendencies of sleep-wake times, and are only considered syndromes if affected individuals complain about life interference, in which case they may fall under the category of

Sleep timing is controlled by the circadian clock, which can entrain to environmental stimuli (usually a light-dark cycle) and is regulated by a transcription-translation feedback loop (TTFL). In humans, there are multiple genes involved in this molecular biological clock, which when mutated may result in sleep disorders such as Familial Advanced Sleep Phase (FASP), Familial Delayed Sleep Phase (FDSP), and Familial Natural Short Sleep (FNSS). Some mutations in Mendelian genes that are involved in the TTFL have been identified as the causes of these sleep traits, including PER2, PER3, CRY2, CRY1.^[2][3] Other Mendelian genes that are not known to play a core role in the TTFL but are involved in FNSS include DEC2 and ADRB1.^[4][5]

With some familial sleep traits, there may be a shift in an individual's chronotype, which describes the time of sleep-wake behaviors that result from circadian rhythms. Chronotype may shift depending on multiple factors including gender and age. Individuals with FASP have earlier chronotypes and individuals with FDSP have later chronotypes compared to a conventional sleep period which runs from approximately 10pm to 7am.^[6] Individuals may meet the criteria for FASP or FDSP if they have Advanced Sleep Phase or Delayed Sleep Phase and at least one first degree relative with the trait. Researchers have examined the human prevalence of FASP to be 0.33-0.5% by including individuals who have a sleep onset at approximately 8:30pm and offset at 5:30am. FDSP, which includes individuals who have a delayed sleep onset and offset, has an unknown human prevalence and may vary based on location, definition, and age.^[6]

History of discoveries

Familial sleep traits have been difficult to study due to the various environmental influences (such as

Another sleep trait, Delayed Sleep Phase Syndrome (DSPS) was first identified by Elliot Weitzman and colleagues in 1981. Individuals with DSPS typically cannot fall asleep until later and wake up later compared to control groups. They often cannot fall asleep until between 2:00-6:00am, but then have a normal sleep duration. However, DSPS was not hypothesized to have a genetic component until researchers at

In addition to these findings, Familial Natural Short Sleep (FNSS) is another heritable sleep trait that has been studied over the past few years. In 2009,

Most of the research conducted thus far has been surrounding FASP, FDSP, and FNSS, with recent studies beginning to examine the roles of heritable sleep variability on

neurodegenerative disease

, has suggested that sleep disruption might contribute to the disease. A characteristic factor of AD is the accumulation of ${\displaystyle A\beta }$ plaques. These plaques are usually at a lower level in the brain interstitial space when an individual first wakes up and then during waking hours these levels increase. Sleep disruption can eliminate the reduction in ${\displaystyle A\beta }$ levels, which is important during disease progression.^[2] Both ASD and AD demonstrate how the heritability of sleep traits may also be involved in disorders and diseases that are not traditionally thought of as circadian, but more research must be done in this field.^[2]

Heritable sleep traits

The functions of heritability for many sleep traits are not well known, underscoring the importance of continued research into the human genome.

Familial Advanced Sleep Phase

Familial Advanced Sleep Phase (FASP) results in an individual having a circadian clock that is entrained to their surroundings, but gives the impression that the individual is not.^[8] This trait typically develops during middle age, and is more common in older adults. Affected individuals typically have a free-running period of about 22 hours, shorter than the average person who has a free-running period closer to 24 hours. This also means that certain physiological markers, such as body temperature and melatonin will be present at higher levels earlier in the day as compared to an average person.^[8]

Symptoms

FASP is typically characterized by excessively early sleep and wake times. Additionally, individuals may experience excessive daytime sleepiness if they are forced to adhere to a schedule offset from their personal biological clock.^[8] Individuals with FASP are typically phase advanced by 4 to 6 hours as compared to the average person.^[6]

Treatments

FASP is traditionally treated with light therapy in the evenings, or behaviorally with chronotherapy. Individuals with FASP typically need to have a two-hour delay per day to remain entrained, due to their 22-hour period. Pharmacological interventions are typically avoided due to risks associated with daytime drug-induced sleepiness.^[14]

Molecular Basis

FASP has been mapped to

Familial Delayed Sleep Phase

Familial Delayed Sleep Phase (FDSP) results in an individual having a circadian clock that is entrained to their surroundings, but gives the impression that the individual is not. The trait typically develops in adolescence.^[16] Affected individuals have a free-running period that is longer than the average 24 hours, meaning that certain physiological markers, such as body temperature and melatonin, are present in higher levels later in the day as compared to the average person.

Symptoms

FDSP is typically characterized by excessively late sleep times and wake times, and may include daytime sleepiness if the individual is forced to adhere to a schedule offset from their personal biological clock. Individuals with FDSP may have comorbidities with depression, Attention Deficit Hyperactivity Disorder (ADHD), obesity, and Obsessive-Compulsive Disorder (OCD).^[17]

Treatments

Treatment is usually non-pharmacological, with light therapy being a common intervention. Phase delay chronotherapy is also occasionally used. Melatonin taken at night will not change the individual's circadian rhythm, but may act as a temporary solution.^[18]

Molecular Basis

FDSP is heritable and linked to mutations in the PER3 and CRY1 genes, which result in the delayed sleep phenotype.^[3]

Fatal Familial Insomnia

Fatal Familial Insomnia (FFI) is a disorder that results in trouble sleeping, speech and coordination problems, and eventually dementia. Most of those affected die within a few years, and the disorder has no cure. The disorder can manifest any time from age 18 to 60, but the average age of affected individuals is 50 years old.^[19]

Symptoms

The disorder has a 4-stage progression, starting with individuals experiencing insomnia, progressing to seeing hallucinations, then inability to sleep and dramatic weight loss, and finally dementia, which is followed by death. Individuals have a 6-36 month prognosis after they begin experiencing symptoms.^[19]

Treatments

Due to the prognosis of the disorder, treatment is often minimal and palliative in nature. Sleeping pills and other traditional treatments are not found to be beneficial in treating FFI.^[20]

Molecular Basis

The disorder is caused by a mutation of the

Familial Natural Short Sleep

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