Advanced sleep phase disorder

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Advanced Sleep Phase Disorder
SymptomsEarlier than desired onset and offset of sleep
Risk factorsSleep deprivation
Diagnostic methodPolysomnography, Horne-Ostberg morningness-eveningness questionnaire
TreatmentBright 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 in which patients feel very sleepy and go to bed early in the evening (e.g. 6:00–8:00 p.m.) and wake up very early in the morning (e.g. around 3:00 a.m.). 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.[1]


Individuals with ASPD report being unable to stay awake until their desired bedtime, falling asleep early in the evening, and being unable to stay asleep until their desired waking time, suffering early morning insomnia. When someone has advanced sleep phase disorder their melatonin levels and core body temperature cycle hours earlier than an average person.[2] These symptoms must be present for substantial periods of time to be correctly diagnosed.


Among other methods, sleep studies, or polysomnography, are used to diagnose ASPD.

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. Age and family history of the patient is also taken into consideration.[1]


Once diagnosed, ASPD can be treated with bright light therapy in the evenings, or behaviorally with chronotherapy, in order to delay sleep onset and offset. Unlike other sleep disorders, ASPD does not necessarily disrupt normal functioning at work during the day and 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.[3]


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. 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 with producing the advanced sleep phase phenotype.[4]  

Familial Advanced Sleep Phase Syndrome[edit]

FASPS Symptoms[edit]

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 circadian period of 22 hours, which is significantly shorter than the average human period of slightly over 24 hours .[5] 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 .[6]

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.[6]

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.[7] Diagnosis of FASPS can be confirmed through genetic sequencing analysis by locating genetic mutations known to cause the disorder. Treatment with light therapy or chronotherapy, as discussed above, can be used to delay sleep phase to a more conventional time frame.


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.[8]

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.[9]

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.[10] FASPS is the first disorder to link known core clock genes directly with human circadian sleep disorders.[11] 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.

Mechanisms (Per2 and CK1)[edit]

A molecular model of the mammalian circadian clock mechanism.

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 revealed a serine-to-glycine point mutation in the Casein Kinase I (CK1) binding domain of the hPER2 protein that resulted in hypophosphorylation of Per2 in vitro (10.1126/science.1057499).[10] The hypophosphorylation of Per2 disrupts the transcription-translation (negative) feedback loop (TTFL) required for regulating the stable production of PER2 protein. Without phosphorylation of hPer2 and production of PER2, the period is shortened to less than 24 hours, producing a phase advance, which would cause people with this mutation to sleep and wake earlier. This is consistent with studies of the role of CK1ɛ in the TTFL in mammals and more studies have been conducted looking at specific regions of the Per2 transcript.[12][13] In 2005, Fu's and Ptáček's labs reported discovery of a mutation in CKIδ also causing FASPS. An A-to-G missense mutation resulted in a threonine-to-alanine alteration in the protein.[14] This mutation prevented the proper phosphorylation of Per2.The evidence for both of these reported causes of FASPS is strengthened by the absence of said mutations in all tested control subjects and by demonstration of functional consequences of the respective mutations in vitro. 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.[14][10]The differences between flies and mammals that account for this difference 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. 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 (10.1016/j.cell.2006.11.043).[15]

See also[edit]


  1. ^ a b Reid KJ, Chang AM, Dubocovich ML, Turek FW, Takahashi JS, Zee PC (July 2001). "Familial advanced sleep phase syndrome". Archives of Neurology. 58 (7): 1089–94. doi:10.1001/archneur.58.7.1089. PMID 11448298.
  2. ^ "Advanced Sleep-Wake Phase Disorder - Symptoms, Diagnosis, Treatment".
  3. ^ Dement WC (1 March 1999). "Advanced Sleep Phase Syndrome". Stanford University.
  4. ^ Zhu L, Zee PC (November 2012). "Circadian rhythm sleep disorders". Neurologic Clinics. 30 (4): 1167–91. doi:10.1016/j.ncl.2012.08.011. PMC 3523094. PMID 23099133.
  5. ^ Jones CR, Huang AL, Ptáček LJ, Fu YH (May 2013). "Genetic basis of human circadian rhythm disorders". Experimental Neurology. 243: 28–33. doi:10.1016/j.expneurol.2012.07.012. PMC 3514403. PMID 22849821.
  6. ^ a b Tafti M, Dauvilliers Y, Overeem S (June 2007). "Narcolepsy and familial advanced sleep-phase syndrome: molecular genetics of sleep disorders". Current Opinion in Genetics & Development. 17 (3): 222–7. doi:10.1016/j.gde.2007.04.007. PMID 17467264.
  7. ^ Pack AI, Pien GW (18 February 2011). "Update on sleep and its disorders". Annual Review of Medicine. 62 (1): 447–60. doi:10.1146/annurev-med-050409-104056. PMID 21073334.
  8. ^ Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptácek LJ (September 1999). "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans". Nature Medicine. 5 (9): 1062–5. doi:10.1038/12502. PMID 10470086.
  9. ^ Reid KJ, Chang AM, Dubocovich ML, Turek FW, Takahashi JS, Zee PC (July 2001). "Familial advanced sleep phase syndrome". Archives of Neurology. 58 (7): 1089–94. doi:10.1001/archneur.58.7.1089. PMID 11448298.
  10. ^ a b c Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH (February 2001). "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome". Science. 291 (5506): 1040–3. Bibcode:2001Sci...291.1040T. doi:10.1126/science.1057499. PMID 11232563.
  11. ^ Takahashi JS, Hong HK, Ko CH, McDearmon EL (October 2008). "The genetics of mammalian circadian order and disorder: implications for physiology and disease". Nature Reviews. Genetics. 9 (10): 764–75. doi:10.1038/nrg2430. PMC 3758473. PMID 18802415.
  12. ^ Ralph MR, Menaker M (September 1988). "A mutation of the circadian system in golden hamsters". Science. 241 (4870): 1225–7. Bibcode:1988Sci...241.1225R. doi:10.1126/science.3413487. PMID 3413487.
  13. ^ Vanselow K, Vanselow JT, Westermark PO, Reischl S, Maier B, Korte T, Herrmann A, Herzel H, Schlosser A, Kramer A (October 2006). "Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)". Genes & Development. 20 (19): 2660–72. doi:10.1101/gad.397006. PMC 1578693. PMID 16983144.
  14. ^ a b Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu YH (March 2005). "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome". Nature. 434 (7033): 640–4. doi:10.1038/nature03453. PMID 15800623.
  15. ^ Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptácek LJ (January 2007). "Modeling of a human circadian mutation yields insights into clock regulation by PER2". Cell. 128 (1): 59–70. doi:10.1016/j.cell.2006.11.043. PMC 1828903. PMID 17218255.

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