title: Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans.
abstract: Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants but none of the human circadian rhythm disorders are known to have a familial tendency. Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults. Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Jones
authors.forename: S S
authors.initials: SS
authors.lastname: Campbell
authors.forename: S E
authors.initials: SE
authors.lastname: Zone
authors.forename: F
authors.initials: F
authors.lastname: Cooper
authors.forename: A
authors.initials: A
authors.lastname: DeSano
authors.forename: P J
authors.initials: PJ
authors.lastname: Murphy
authors.forename: B
authors.initials: B
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: Czajkowski
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
mesh_terms: D000204:Activity Cycles; D000328:Adult; D000368:Aged; D002648:Child; D002940:Circadian Rhythm / Q000235:genetics*; D005060:Europe; D005192:Family Health; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008550:Melatonin / Q000032:analysis; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D017286:Polysomnography; D012890:Sleep / Q000235:genetics; D012894:Sleep Stages; D012893:Sleep Wake Disorders / Q000235:genetics*; D013696:Temperature; D013997:Time Factors
chemical_list: D008550:Melatonin