Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans

Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipatin g the transitions between day and night. The circadian rhythms of sleep, me latonin 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(1,2). Autosomal semi-dominant mutations in rodent s with fast or slow biological clocks (that is, short or long endogenous pe riod lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial huma n circadian rhythm variants(3,4) but none of the human circadian rhythm dis orders are known to have a familial tendency(5). Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep pha se-advance are rare. This disorder, advanced sleep-phase syndrome, is chara cterized by very early sleep onset and offset; only two cases are reported in young adults(6,7). Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated wi th a very short tau. The trait segregates as an autosomal dominant with hig h penetrance. These kindreds represent a well-characterized familial circad ian rhythm variant in humans and provide a unique opportunity for genetic a nalysis of human circadian physiology.