Editing Advanced sleep phase disorder (section)

==Familial advanced sleep phase syndrome==

=== FASPS symptoms ===
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 clock|circadian period]] of 22 hours, which is significantly shorter than the average human period of slightly over 24 hours.<ref>{{Cite journal|last1=Jones|first1=Christopher R.|last2=Huang|first2=Angela L.|last3=Ptáček|first3=Louis J.|last4=Fu|first4=Ying-Hui|date=2013|title=Genetic Basis of Human Circadian Rhythm Disorders|journal=Experimental Neurology|volume=243|pages=28–33|doi=10.1016/j.expneurol.2012.07.012|issn=0014-4886|pmc=3514403|pmid=22849821}}</ref> 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.<ref name=":0">{{Cite journal|last1=Tafti|first1=Mehdi|last2=Dauvilliers|first2=Yves|last3=Overeem|first3=Sebastiaan|date=2007|title=Narcolepsy and familial advanced sleep-phase syndrome: molecular genetics of sleep disorders|journal=Current Opinion in Genetics & Development|language=en|volume=17|issue=3|pages=222–227|doi=10.1016/j.gde.2007.04.007|pmid=17467264}}</ref>

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.<ref name=":0" />

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 [[Dominance (genetics)|autosomal dominant trait]].<ref>{{Cite journal|last1=Pack|first1=Allan I.|last2=Pien|first2=Grace W.|date=18 February 2011|title=Update on Sleep and Its Disorders|journal=Annual Review of Medicine|language=en|volume=62|issue=1|pages=447–460|doi=10.1146/annurev-med-050409-104056|pmid=21073334|issn=0066-4219}}</ref> 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.<ref>{{Cite journal|last1=Fu|first1=Y. H.|last2=Ptáček|first2=L. J.|last3=Chong|first3=S. Y.|date=2012|title=Genetic insights on sleep schedules: this time, it's PERsonal.|journal=Trends in Genetics|volume=28|issue=12|pages=598–605|doi=10.1016/j.tig.2012.08.002|issn=0168-9525|pmid=22939700|pmc=3500418}}</ref> 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,<ref name=":33"/> has been shown to delay circadian rhythms, resulting in later sleep onset and offset in patients with FASPS or other advanced sleep phase disorders.<ref name=":25"/>

=== Discovery ===
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 [[Morningness–eveningness questionnaire|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 chart|pedigree]] of the three FASPS kindreds which indicated a clear [[Dominance (genetics)|autosomal dominant]] transmission of the sleep phase advance.<ref>{{Cite journal|last1=Jones|first1=Christopher R.|last2=Campbell|first2=Scott S.|last3=Zone|first3=Stephanie E.|last4=Cooper|first4=Fred|last5=DeSano|first5=Alison|last6=Murphy|first6=Patricia J.|last7=Jones|first7=Bryan|last8=Czajkowski|first8=Laura|last9=Ptček|first9=Louis J.|date=1999|title=Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans|journal=Nature Medicine|language=en|volume=5|issue=9|pages=1062–1065|doi=10.1038/12502|pmid=10470086|s2cid=14809619|issn=1078-8956}}</ref>

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 [[Neuroscience of sleep|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.<ref name=":13">{{Cite journal|last1=Reid|first1=Kathryn J.|last2=Chang|first2=Anne-Marie|last3=Dubocovich|first3=Margarita L.|last4=Turek|first4=Fred W.|last5=Takahashi|first5=Joseph S.|last6=Zee|first6=Phyllis C.|date=1 July 2001|title=Familial Advanced Sleep Phase Syndrome|journal=Archives of Neurology|language=en|volume=58|issue=7|pages=1089–94|doi=10.1001/archneur.58.7.1089|pmid=11448298|issn=0003-9942|doi-access=free}}</ref>

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 [[Casein kinase 1|CK1]]-binding region of [[PER2]] in producing the FASPS behavioral phenotype.<ref name=":42">{{Cite journal|last=Toh|first=K. L.|date=9 February 2001|title=An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome|journal=Science|volume=291|issue=5506|pages=1040–1043|doi=10.1126/science.1057499|pmid=11232563|bibcode=2001Sci...291.1040T|s2cid=1848310}}</ref> FASPS is the first disorder to link known core clock genes directly with human circadian sleep disorders.<ref>{{Cite journal|last1=Takahashi|first1=Joseph S.|last2=Hong|first2=Hee-Kyung|last3=Ko|first3=Caroline H.|last4=McDearmon|first4=Erin L.|date=2008|title=The genetics of mammalian circadian order and disorder: implications for physiology and disease|journal=Nature Reviews Genetics|language=en|volume=9|issue=10|pages=764–775|doi=10.1038/nrg2430|issn=1471-0056|pmc=3758473|pmid=18802415}}</ref> 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|date=July 2021}}

=== Mechanisms (Per2 and CK1) ===
[[File:Circadian clock of mammals.PNG|thumb|300x300px|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 2]]q 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 [[PER2|''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 1|Casein Kinase I]] (CK1) [[binding domain]] of the hPER2 protein that resulted in [[Phosphorylation|hypophosphorylation]] of hPER2 in vitro.<ref name=":42"/> The hypophosphorylation of hPER2 disrupts the transcription-translation [[Negative feedback|(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|date=July 2021}}

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|Phase Response Curve (PRC)]].<ref>{{Cite journal|last=Johnson|first=Carl H.|date=2013|title=Entrainment of Circadian Programs|url=https://as.vanderbilt.edu/johnsonlab/publications/reprints/2003review_entrainment.pdf|journal=Chronobiology International|volume=20|issue=5|pages=741–774|doi=10.1081/CBI-120024211|pmid=14535352|s2cid=16424964}}</ref> This is consistent with studies of the role of CK1ɛ (a unique member of the CK1 family)<ref>{{Cite journal|last1=Yang|first1=Yu|last2=Xu|first2=Tingting|last3=Zhang|first3=Yunfei|last4=Qin|first4=Ximing|date=2017|title=Molecular basis for the regulation of the circadian clock kinases CK1δ and CK1ε|journal=Cellular Signalling|volume=31|pages=58–65|doi=10.1016/j.cellsig.2016.12.010|pmid=28057520|issn=0898-6568}}</ref> in the TTFL in mammals and more studies have been conducted looking at specific regions of the Per2 transcript.<ref>{{Cite journal|last1=Vanselow|first1=Katja|last2=Vanselow|first2=Jens T.|last3=Westermark|first3=Pål O.|last4=Reischl|first4=Silke|last5=Maier|first5=Bert|last6=Korte|first6=Thomas|last7=Herrmann|first7=Andreas|last8=Herzel|first8=Hanspeter|last9=Schlosser|first9=Andreas|date=1 October 2006|title=Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)|journal=Genes & Development|volume=20|issue=19|pages=2660–2672|doi=10.1101/gad.397006|issn=0890-9369|pmc=1578693|pmid=16983144}}</ref><ref>{{Cite journal|last1=Menaker|first1=M.|last2=Ralph|first2=M. R.|date=2 September 1988|title=A mutation of the circadian system in golden hamsters|journal=Science|language=en|volume=241|issue=4870|pages=1225–1227|doi=10.1126/science.3413487|issn=0036-8075|pmid=3413487|bibcode=1988Sci...241.1225R}}</ref> 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.<ref name="xu22">{{cite journal|last=Xu|first=Ying|author2=Kong L. Toh|author3=Christopher R. Jones|display-authors=etal|date=12 January 2007|title=Modeling of a human circadian mutation yields insights into clock regulation by PER2|url= |journal=Cell|volume=128|issue=1|pages=59–70|doi=10.1016/j.cell.2006.11.043|pmc=1828903|pmid=17218255}}</ref> 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.<ref name="xu3">{{cite journal|last=Xu|first=Ying|author2=Quasar S. Padiath|author3=Robert E. Shapiro|display-authors=etal|date=31 March 2005|title=Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome|journal=Nature|volume=434|issue=7033|pages=640–644|doi=10.1038/nature03453|pmid=15800623|bibcode=2005Natur.434..640X|s2cid=4416575}}</ref><ref name=":42"/> 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.<ref>{{Cite journal|last1=Xu|first1=Y.|last2=Toh|first2=K.L.|last3=Jones|first3=C.R.|last4=Shin|first4=J.-Y.|last5=Fu|first5=Y.-H.|last6=Ptáček|first6=L.J.|date=2007|title=Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2|journal=Cell|language=en|volume=128|issue=1|pages=59–70|doi=10.1016/j.cell.2006.11.043|pmc=1828903|pmid=17218255}}</ref>