Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 5, pages 1062–1065 (1999)Cite this article

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 clock1,2. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; τ) are associated with phase-advanced or delayed sleep–wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants3,4 but none of the human circadian rhythm disorders are known to have a familial tendency5. 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 adults6,7. Here we describe three kindreds with a profound phase advance of the sleep–wake, melatonin and temperature rhythms associated with a very short τ. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pedigrees of three FASPS kindreds.
Figure 2: Free-running period of the circadian sleep–wake and temperature rhythms in one FASPS subject.

Similar content being viewed by others

References

  1. Shanahan, T.L. & Czeisler, C.A. Light exposure induces equivalent phase shifts of the endogenous circadian rhythms of circulating plasma melatonin and core body temperature in men. J. Clin. Endocrinol. Metab. 73, 27–35 (1991).

    Article  Google Scholar 

  2. Czeisler, C.A., Weitzman, E., Moore-Ede, M.C., Zimmerman, J.C. & Knauer, R.S. Human sleep: its duration and organization depend on its circadian phase. Science 210, 1264–1267 (1980).

    Article  CAS  Google Scholar 

  3. Ralph, M.R. & Menaker, M. A mutation of the circadian system in golden hamsters. Science 241, 1225– 1227 (1988).

    Article  CAS  Google Scholar 

  4. Vitaterna, M.H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719 –725 (1994).

    Article  CAS  Google Scholar 

  5. American Sleep Disorders Association in International Classification of Sleep Disorders: (Revised): Diagnostic and Coding Manual (Chairman, Thorphy, M.J.) 133– 136 (Rochester, Minnesota,1997).

  6. Billiard, M. et al. A case of advanced-sleep phase syndrome. Sleep Res. 22, 109 (1993).

    Google Scholar 

  7. Singer, C.M. & Lewy, A.J. Case report: Use of the dim light melatonin onset in the treatment of ASPS with bright light. Sleep Res. 18, 445 (1989).

    Google Scholar 

  8. Horne, J.A. & Östberg, O. A self-assessment questionnaire to determine morningness- eveningness in human circadian rhythms. Int. J. Chronobiol. 4, 97–110 (1976).

    CAS  PubMed  Google Scholar 

  9. Beck, A.T. The Beck Depression Inventory (BDI-II) 1–2 (Harcourt Brace & Company, San Antonio, Texas, 1978).

    Google Scholar 

  10. Keenan, S.A. in Sleep Disorders Medicine: Basic Science, Technical Considerations and Clinical Aspects (ed. Chockroverty S) 79–94 (Butterworth-Heinemann, Boston, 1994).

    Book  Google Scholar 

  11. Rechtschaffen, A. & Kales, A. in A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects (eds. Rechtschaffen, A. & Kales, A.) 1–12 (UCLA Brain Information Service/Brain Research Institute, Los Angeles, 1968).

    Google Scholar 

  12. Carskadon, M.A. et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 9, 519– 524 (1986).

    Article  CAS  Google Scholar 

  13. Lewy, A.J. & Sack, R.L. The dim light melatonin onset as a marker for circadian phase position. Chronobiol. Int. 6, 93–102 (1989).

    Article  CAS  Google Scholar 

  14. Campbell, S.S., Dawson, D. & Zulley, J. When the human circadian system is caught napping: evidence for endogenous rhythms close to 24 hours. Sleep 16, 638–640 (1993).

    CAS  PubMed  Google Scholar 

  15. Carskadon, M.A. & Dement, W.C. Sleep studies on a 90-minute day. Electroencephalogr. Clin. Neurophysiol. 39, 145–155 (1975).

    Article  CAS  Google Scholar 

  16. Lavie, P. Ultrashort sleep-waking schedule. III. 'Gates' and 'forbidden zones' for sleep. Electroencephalogr. Clin. Neurophysiol. 63, 414–425 (1986).

    Article  CAS  Google Scholar 

  17. Greenwood, K.M. Long-term stability and psychometric properties of the composite scale of morningness. Ergonomics 37, 377– 383 (1994).

    Article  CAS  Google Scholar 

  18. Campbell, S.S., Gillin, J.C., Kripke, D.F., Erikson, P. & Clopton, P. Gender differences in the circadian temperature rhythms of healthy elderly subjects: relationships to sleep quality. Sleep 12, 529–536 (1989 ).

  19. Haimov, I. & Lavie, P. Circadian characteristics of sleep propensity function in healthy elderly: a comparison with young adults. Sleep 20, 294–300 ( 1997).

    Article  CAS  Google Scholar 

  20. Drennan, M.D., Selby, J., Kripke, D.F., Kelsoe, J. & Gillin, J.C. Morningness/eveningness is heritable. Soc. Neurosci. Abstr. 18, 196 ( 1992).

    Google Scholar 

  21. Katzenberg, D. et al. A CLOCK polymorphism associated with human diurnal preference. Sleep 21, 569–576 (1998).

    Article  CAS  Google Scholar 

  22. Klerman, E.B., Dijk, D.J., Kronauer, R.E. & Czeisler, C.A. Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period. Am. J. Physiol. 270, R271–282 (1996).

    CAS  PubMed  Google Scholar 

  23. Duffy, J.F., Rimmer, D.W., Silva, E.J. & Czeisler, C.A. Correlation of intrinsic circadian period with morningness-eveningness in young men. Sleep 22, S92 ( 1999).

    Google Scholar 

  24. Darlington, T.K. et al. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280, 1599–1603 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank A.J. Lewy, who provided discussions and comments,and A. Dean and T. Schenkenberg for critical reading of this manuscript. This investigation was supported by NIH grant HL/HD 59596 (L.J.P.) and Public Health Service research grant M01-RR00064 from the National Center for Research Resources.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Utah, Salt Lake City, 84112, Utah, USA

    Christopher R. Jones & Louis J. Ptček

  2. University Hospital Sleep Disorders Center, University of Utah, Salt Lake City, 84112, Utah, USA

    Christopher R. Jones

  3. Howard Hughes Medical Institute, University of Utah, Salt Lake City, 84112, Utah, USA

    Stephanie E. Zone, Alison DeSano & Louis J. Ptček

  4. Department of Management; David Eccles School of Business, University of Utah,

    Fred Cooper

  5. David Eccles School of Business, University of Utah, Salt Lake City, 84112, Utah, USA

    Fred Cooper

  6. Department of Physiology, University of Utah, Salt Lake City, 84112, Utah, USA

    Bryan Jones

  7. Department of Psychiatry, University of Utah, Salt Lake City, 84112, Utah, USA

    Laura Czajkowski

  8. Department of Human Genetics, University of Utah, Salt Lake City, 84112, Utah, USA

    Louis J. Ptček

  9. Program in Neuroscience, University of Utah, Salt Lake City, 84112, Utah, USA

    Louis J. Ptček

  10. Department of Psychiatry, Weill Medical College of Cornell University, White Plains, 10605, New York, USA

    Scott S. Campbell & Patricia J. Murphy

Authors
  1. Christopher R. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott S. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie E. Zone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fred Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alison DeSano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patricia J. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bryan Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laura Czajkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Louis J. Ptček
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jones, C., Campbell, S., Zone, S. et al. Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nat Med 5, 1062–1065 (1999). https://doi.org/10.1038/12502

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/12502

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing