| Advanced Sleep Phase Disorder | |
|---|---|
| Specialty | Chronobiology |
| Symptoms | Earlier than desired onset and offset of sleep |
| Complications | Sleep deprivation |
| Risk factors | Increased incidence with age |
| Diagnostic method | Polysomnography, Horne-Ostberg morningness-eveningness questionnaire |
| Treatment | Bright light therapy, chronotherapy |
Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early morning awakening (e.g. 2-4 AM). This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. [1] The timing of sleep and melatonin levels are regulated by the body's central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus. [2]
Individuals with ASPD report being unable to stay awake until conventional bedtime, falling asleep too quickly and/or early in the evening, and being unable to stay asleep until their desired waking time, experiencing early morning insomnia. When someone has advanced sleep phase disorder their melatonin levels and core body temperature cycle hours earlier than an average person. [3] These symptoms must be present and stable for a substantial period of time to be correctly diagnosed.[ citation needed ]
Individuals expressing the above symptoms may be diagnosed with ASPD using a variety of methods and tests. Sleep specialists measure the patient's sleep onset and offset, dim light melatonin onset, and evaluate Horne-Ostberg morningness-eveningness questionnaire results. Sleep specialists may also conduct a polysomnography test to rule out other sleep disorders like narcolepsy. Age and family history of the patient is also taken into consideration. [2]
Once diagnosed, ASPD may be treated with bright light therapy in the evenings, or behaviorally with chronotherapy, in order to delay sleep onset and offset. The use of pharmacological approaches to treatment are less successful due to the risks of administering sleep-promoting agents early in the morning. [1] Additional methods of treatment, like timed melatonin administration or hypnotics have been proposed, but determining their safety and efficacy will require further research. [4] Unlike other sleep disorders, ASPD does not necessarily disrupt normal functioning at work during the day and some patients may not complain of excessive daytime sleepiness. Social obligations may cause an individual to stay up later than their circadian rhythm requires, however, they will still wake up very early. If this cycle continues, it can lead to chronic sleep deprivation and other sleep disorders.[ citation needed ]
ASPD is more common among middle and older adults. The estimated prevalence of ASPD is about 1% in middle-age adults, and is believed to affect men and women equally. The disorder has a strong familial tendency, with 40-50% of affected individuals having relatives with ASPD. [5] A genetic basis has been demonstrated in one form of ASPD, familial advanced sleep phase disorder (FASPS), which implicates missense mutations in genes hPER2 and CKIdelta in producing the advanced sleep phase phenotype. [5] The identification of two different genetic mutations suggests that there is heterogeneity of this disorder. [1]
While advanced sleep and wake times are relatively common, especially among older adults, the extreme phase advance characteristic of familial advanced sleep phase syndrome (also known as familial advanced sleep phase disorder) is rare. Individuals with FASPS fall asleep and wake up 4–6 hours earlier than the average population, generally sleeping from 7:30pm to 4:30am. They also have a free running circadian period of 22 hours, which is significantly shorter than the average human period of slightly over 24 hours. [6] The shortened period associated with FASPS results in a shortened period of activity, causing earlier sleep onset and offset. This means that individuals with FASPS must delay their sleep onset and offset each day in order to entrain to the 24-hour day. On holidays and weekends, when the average person's sleep phase is delayed relative to their workday sleep phase, individuals with FASPS experience further advance in their sleep phase. [7]
Aside from the unusual timing of sleep, FASPS patients experience normal quality and quantity of sleep. Like general ASPD, this syndrome does not inherently cause negative impacts, however, sleep deprivation may be imposed by social norms causing individuals to delay sleep until a more socially acceptable time, causing them to losing sleep due to earlier-than-usual wakeup time. [7]
Another factor that distinguishes FASPS from other advanced sleep phase disorders is its strong familial tendency and life-long expression. Studies of affected lineages have found that approximately 50% of directly related family members experience the symptoms of FASPS, which is an autosomal dominant trait. [8] Diagnosis of FASPS can be confirmed through genetic sequencing analysis by locating genetic mutations known to cause the disorder. Treatment with sleep and wake scheduling and bright light therapy can be used to try to delay sleep phase to a more conventional time frame, however treatment of FASPS has proven largely unsuccessful. [9] Bright light exposure in the evening (between 7:00 and 9:00), during the delay zone as indicated by the phase response curve to light, [5] has been shown to delay circadian rhythms, resulting in later sleep onset and offset in patients with FASPS or other advanced sleep phase disorders. [1]
In 1999, Louis Ptáček conducted a study at the University of Utah in which he coined the term familial advanced sleep phase disorder after identifying individuals with a genetic basis for an advanced sleep phase. The first patient evaluated during the study reported "disabling early evening sleepiness" and "early morning awakening"; similar symptoms were also reported in her family members. Consenting relatives of the initial patient were evaluated, as well as those from two additional families. The clinical histories, sleep logs and actigraphy patterns of subject families were used to define a hereditary circadian rhythm variant associated with a short endogenous (i.e. internally-derived) period. The subjects demonstrated a phase advance of sleep-wake rhythms that was distinct not only from control subjects, but also to sleep-wake schedules widely considered to be conventional. The subjects were also evaluated using the Horne-Östberg questionnaire, a structured self-assessment questionnaire used to determine morningness-eveningness in human circadian rhythms. The Horne-Östberg scores of first-degree relatives of affected individuals were higher than those of 'marry-in' spouses and unrelated control subjects. While much of morning and evening preference is heritable, the allele causing FASPS was hypothesized to have a quantitatively larger effect on clock function than the more common genetic variations that influence these preferences. Additionally, the circadian phase of subjects was determined using plasma melatonin and body core temperature measurements; these rhythms were both phase-advanced by 3–4 hours in FASPS subjects compared with control subjects. The Ptáček group also constructed a pedigree of the three FASPS kindreds which indicated a clear autosomal dominant transmission of the sleep phase advance. [10]
In 2001, the research group of Phyllis C. Zee phenotypically characterized an additional family affected with ASPS. This study involved an analysis of sleep/wake patterns, diurnal preferences (using a Horne-Östberg questionnaire), and the construction of a pedigree for the affected family. Consistent with established ASPS criteria, the evaluation of subject sleep architecture indicated that the advanced sleep phase was due to an alteration of circadian timing rather than an exogenous (i.e. externally-derived) disruption of sleep homeostasis, a mechanism of sleep regulation. Furthermore, the identified family was one in which an ASPS-affected member was present in every generation; consistent with earlier work done by the Ptáček group, this pattern suggests that the phenotype segregates as a single gene with an autosomal dominant mode of inheritance. [11]
In 2001, the research groups of Ptáček and Ying-Hui Fu published a genetic analysis of subjects experiencing the advanced sleep phase, implicating a mutation in the CK1-binding region of PER2 in producing the FASPS behavioral phenotype. [12] FASPS is the first disorder to link known core clock genes directly with human circadian sleep disorders. [13] As the PER2 mutation is not exclusively responsible for causing FASPS, current research has continued to evaluate cases in order to identify new mutations that contribute to the disorder.[ citation needed ]
Two years after reporting the finding of FASPS, Ptáček's and Fu's groups published results of genetic sequencing analysis on a family with FASPS. They genetically mapped the FASPS locus to chromosome 2q where very little human genome sequencing was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2) which is a mammalian gene sufficient for the maintenance of circadian rhythms. Sequencing of the hPer2 gene ('h' denoting a human strain, as opposed to Drosophila or mouse strains) revealed a serine-to-glycine point mutation in the Casein Kinase I (CK1) binding domain of the hPER2 protein that resulted in hypophosphorylation of hPER2 in vitro. [12] The hypophosphorylation of hPER2 disrupts the transcription-translation (negative) feedback loop (TTFL) required for regulating the stable production of hPER2 protein. In a wildtype individual, Per2 mRNA is transcribed and translated to form a PER2 protein. Large concentrations of PER2 protein inhibits further transcription of Per2 mRNA. CK1 regulates PER2 levels by binding to a CK1 binding site on the protein, allowing for phosphorylation which marks the protein for degradation, reducing protein levels. Once proteins become phosphorylated, PER2 levels decrease again, and Per2 mRNA transcription can resume. This negative feedback regulates the levels and expression of these circadian clock components.[ citation needed ]
Without proper phosphorylation of hPER2 in the instance of a mutation in the CK1 binding site, less Per2 mRNA is transcribed and the period is shortened to less than 24 hours. Individuals with a shortened period due to this phosphorylation disruption entrain to a 24h light-dark cycle, which may lead to a phase advance, causing earlier sleep and wake patterns. However, a 22h period does not necessitate a phase shift, but a shift can be predicted depending on the time the subject is exposed to the stimulus, visualized on a Phase Response Curve (PRC). [14] This is consistent with studies of the role of CK1ɛ (a unique member of the CK1 family) [15] in the TTFL in mammals and more studies have been conducted looking at specific regions of the Per2 transcript. [16] [17] In 2005, Fu's and Ptáček's labs reported discovery of a mutation in CKIδ (a functionally redundant form of CK1ɛ in the phosphorylation process of PER2) also causing FASPS. An A-to-G missense mutation resulted in a threonine-to-alanine alteration in the protein. [18] This mutation prevented the proper phosphorylation of PER2. The evidence for both a mutation in the binding domain of PER2 and a mutation in CKIδ as causes of FASPS is strengthened by the lack of the FASPS phenotype in wild type individuals and by the observed change in the circadian phenotype of these mutant individuals in vitro and an absence of said mutations in all tested control subjects. Fruit flies and mice engineered to carry the human mutation also demonstrated abnormal circadian phenotypes, although the mutant flies had a long circadian period while the mutant mice had a shorter period. [19] [12] The genetic differences between flies and mammals that account for this difference circadian phenotypes are not known. Most recently, Ptáček and Fu reported additional studies of the human Per2 S662G mutation and generation of mice carrying the human mutation. These mice had a circadian period almost 2 hours shorter than wild-type animals under constant darkness. Genetic dosage studies of CKIδ on the Per2 S662G mutation revealed that depending on the binding site on Per2 that CK1δ interacts with, CK1δ may lead to hypo- or hyperphosphorylation of the Per2 gene. [20]
A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.
Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is the delaying of a person's circadian rhythm compared to those of societal norms. The disorder affects the timing of biological rhythms including sleep, peak period of alertness, core body temperature, and hormonal cycles.
The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. The SCN is the principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow the SCN to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.
Non-24-hour sleep–wake disorder is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising [...] daily delays in sleep onset and wake times in an individual living in a society". Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. Although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. The American Academy of Sleep Medicine (AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015.
Smith–Magenis syndrome (SMS), also known as 17p- syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, difficulty sleeping, and numerous behavioral problems such as self-harm. Smith–Magenis syndrome affects an estimated between 1 in 15,000 to 1 in 25,000 individuals.
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in one's biological clock system, or by misalignment between one's endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.
The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.
Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.
The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.
PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.
In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.
Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the double-time protein in fruit flies. Michael Young and his team at Rockefeller University Rockefeller University first identified and characterized the gene in 1998.
Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.
Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.
Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.
Louis Ptáček is an American neurologist and professor who contributed greatly to the field of genetics and neuroscience. He was also an HHMI investigator from 1997 to 2018. His chief areas of research include the understanding of inherited Mendelian disorders and circadian rhythm genes. Currently, Ptáček is a neurology professor and a director of the Division of Neurogenetics in University of California, San Francisco, School of Medicine. His current investigations primarily focus on extensive clinical studies in families with hereditary disorders, which include identifying and characterizing the genes responsible for neurological variations.
Achim Kramer is a German chronobiologist and biochemist. He is the current head of Chronobiology at Charité – Universitätsmedizin Berlin in Berlin, Germany.
Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.
Carrie L. Partch is an American protein biochemist and circadian biologist. Partch is currently a Professor in the Department of Chemistry and Biochemistry at the University of California, Santa Cruz. She is noted for her work using biochemical and biophysical techniques to study the mechanisms of circadian rhythmicity across multiple organisms. Partch applies principles of chemistry and physics to further her research in the field of biological clocks.
Familial natural short sleep is a rare, genetic, typically inherited trait where an individual sleeps for fewer hours than average without suffering from daytime sleepiness or other consequences of sleep deprivation. This process is entirely natural in this kind of individual, and it is caused by certain genetic mutations. A person with this trait is known as a "natural short sleeper".