Non-24-h sleep-wake disorder (N24SWD) is a rare circadian rhythm disorder in sighted patients whose underlying pathophysiology remains poorly understood. Here, we aimed to investigate the mechanisms of impaired circadian entrainment by combining assessments of retinal and melanopsin function, circadian light responsiveness and endogenous circadian rhythmicity. Two sighted patients with confirmed N24SWD underwent comprehensive circadian phenotyping targeting three complementary components of the circadian system: retinal and melanopsin-mediated photoreception, endogenous circadian timing, and circadian responsiveness to light. Retinal function was assessed using full-field electroretinography and chromatic pupillometry with measurement of the post-illumination pupil response (PIPR). Endogenous circadian phase and period were characterized through continuous core body temperature monitoring and hourly plasma melatonin and cortisol sampling during a 25-h multiple-nap protocol conducted under modified constant-routine conditions. Circadian light responsiveness was evaluated using three 15-min light exposures delivered at different irradiance levels and circadian phases across three consecutive nights, with simultaneous assessment of light-induced melatonin suppression. The first subject exhibited preserved melanopsinergic response as indicated by a normal PIPR, but showed no melatonin suppression regardless of light timing or illuminance levels. The intrinsic circadian period of melatonin and temperature was markedly prolonged (≈25 h). In contrast, the second patient exhibited impaired melanopsinergic response, reflected by reduced PIPR, while retaining melatonin suppression across all light conditions. His intrinsic period remained within the upper physiological range (24.20 h). This first multimodal characterization of sighted N24SWD reveals distinct pathophysiological mechanisms underlying failure of photic circadian entrainment. These observations suggest that N24SWD in sighted individuals should not be considered a unitary disorder but rather a heterogeneous condition resulting from dysfunction at different levels of the circadian photic entrainment pathway. Such mechanistic phenotyping may provide a foundation for personalized therapeutic strategies targeting the specific component of the circadian system that is impaired.
Circadian Biology