Pathophysiology and strategic treatment of sighted non-24-h sleep–wake rhythm disorders

Non-24-h sleep–wake rhythm disorder (N24SWD) is one type of circadian rhythm sleep–wake disorder. Once developed, N24SWD causes occupational and social dysfunction due to its early onset, long-term morbidity, and intractable nature, imposing a huge burden on individuals with the disorder. N24SWD is highly prevalent in blind individuals who have had no photic entrainment. The pathophysiology of sighted N24SWD in individuals with no visual impairment is unclear, but as a concept, impaired entrainment to the 24-h day–night cycle or abnormality in the free-running period (τ) was thought to be the cause of N24SWD. A recent study using a strict forced desynchrony protocol revealed prolonged τ in sighted N24SWD patients. In contrast, some evening chronotypes are able to entrain to the 24-h-day cycle despite having similarly prolonged τ. Therefore, the onset of N24SWD could be reasonably explained by the multiple-hit hypothesis, which proposes that disease onset requires the coexistence of multiple vulnerabilities, such as prolonged τ, abnormal photosensitivity, overexposure to ambient light in the delay zone of the phase response curve, and psychiatric problems. The application of a molecular genetic approach similar to that used in the study of advanced sleep–wake phase disorder is difficult because of the absence of familial occurrence in most sighted N24SWD patients. However, a different experimental approach such as whole-exome analysis of individual cases may be useful for clarifying the molecular basis underlying the onset of sighted N24SWD.