HormonesMelatonin

Sighted non-24-hour sleep-wake disorder is a heterogeneous condition caused by distinct dysfunctions in the circadian photic entrainment pathway

This multimodal phenotyping of two sighted N24SWD patients revealed two distinct pathophysiological mechanisms: one patient had preserved melanopsin function but absent light-induced melatonin suppression and a markedly prolonged intrinsic period (~25 h), while the other had impaired melanopsin response (reduced PIPR) but retained melatonin suppression and a period within the upper physiological range (24.20 h). These findings indicate that N24SWD in sighted individuals is not a unitary disorder but results from dysfunction at different levels of the circadian photic entrainment pathway.

Last updated: Aug 26, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score32/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Multimodal circadian phenotyping reveals distinct mechanisms of photic entrainment failure in two sighted patients with non-24-hour sleep-wake disorder.

observational

Kilic Huck Ü, Vasseur F, Braun Hughes S, Morris F, Comtet H, Hugueny L, Reix N, Geoffroy PA, Bourgin P · Sleep medicine (2026)

Participants: N/A
Duration: Not specified (multiple nights of testing)
Intervention: Comprehensive circadian phenotyping including full-field electroretinography, chromatic pupillometry, 25-h multiple-nap protocol under modified constant routine, and three 15-min light exposures at different irradiance levels and circadian phases
Outcome: Melanopsin function (PIPR), endogenous circadian period (melatonin, cortisol, core body temperature), and light-induced melatonin suppression
Effect Size: N/A
Population: Two sighted patients with confirmed non-24-hour sleep-wake disorder

Result:

PubMed: 42612567DOI: 10.1016/j.sleep.2026.109204

Mechanism Graph

Patient 1: Normal melanopsin response (normal PIPR), but no melatonin suppression regardless of light timing or illuminance
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Patient 1: Intrinsic circadian period markedly prolonged (~25 h)
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Patient 2: Impaired melanopsin response (reduced PIPR), but melatonin suppression retained across all light conditions
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Patient 2: Intrinsic period within upper physiological range (24.20 h)
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Result: Distinct pathophysiological mechanisms underlie failure of photic entrainment in sighted N24SWD

Limitations

  • ⚠Only two patients were studied, limiting generalizability
  • ⚠No control group for comparison
  • ⚠The study is descriptive and does not establish causality
  • ⚠The light exposure protocol was limited to three 15-min exposures, which may not capture full circadian light responsiveness

Frequently Asked Questions

What is non-24-hour sleep-wake disorder (N24SWD)?▼

N24SWD is a rare circadian rhythm disorder where the internal body clock is not aligned with the 24-hour day, leading to progressive delays in sleep-wake timing. It is most common in blind individuals but can occur in sighted people.

What are the two distinct mechanisms of photic entrainment failure identified in this study?▼

The first mechanism involves a normal melanopsin response but a failure of light to suppress melatonin, combined with a very long intrinsic period (~25 h). The second mechanism involves impaired melanopsin function (reduced PIPR) but preserved melatonin suppression, with a period in the upper normal range (24.20 h).

How was circadian light responsiveness measured?▼

Circadian light responsiveness was evaluated using three 15-minute light exposures at different irradiance levels and circadian phases across three consecutive nights, with simultaneous measurement of light-induced melatonin suppression.

What is the clinical implication of this study?▼

The findings suggest that sighted N24SWD is heterogeneous, and mechanistic phenotyping could guide personalized treatment targeting the specific impaired component of the circadian system, such as melanopsin function or light responsiveness.

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References

  1. 1.Kilic Huck Ü, Vasseur F, Braun Hughes S, Morris F, Comtet H, Hugueny L, Reix N, Geoffroy PA, Bourgin P. "Multimodal circadian phenotyping reveals distinct mechanisms of photic entrainment failure in two sighted patients with non-24-hour sleep-wake disorder.." Sleep medicine, 2026. PMID: 42612567 DOI: 10.1016/j.sleep.2026.109204
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