Melatonin alterations and brain acetylcholine lesions in sleep disorders in Cockayne syndrome

• Published in: Brain & development (Tokyo. 1979) Vol. 36; no. 10; pp. 907 - 913
• Main Authors: Okoshi, Yumi, Tanuma, Naoyuki, Miyata, Rie, Hayashi, Masaharu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2014
• Subjects: Acetylcholine; Acetylcholine - metabolism; Adolescent; Adult; Antioxidants - therapeutic use; Brain - drug effects; Brain - metabolism; Brain - ultrastructure; Case-Control Studies; Child; Child, Preschool; Cockayne syndrome; Cockayne Syndrome - complications; Female; Humans; Hypothalamus; Immunohistochemistry; Male; Melatonin; Melatonin - analogs & derivatives; Melatonin - metabolism; Melatonin - therapeutic use; Melatonin - urine; Microscopy, Electron, Transmission; Nerve Tissue Proteins - metabolism; Neurology; Sleep disorders; Sleep Wake Disorders - drug therapy; Sleep Wake Disorders - etiology; Sleep Wake Disorders - pathology; Surveys and Questionnaires; Young Adult; Immunohistochemistry; Cockayne syndrome; Sleep disorders; Melatonin; Acetylcholine; Hypothalamus
• ISSN: 0387-7604; 1872-7131
• DOI: 10.1016/j.braindev.2014.01.004

Abstract Background: Cockayne syndrome (CS) is a genetic disorder caused by deficient nucleotide excision repair. Patients with CS exhibit progeroid features, developmental delay, and various neurological disorders; they are also known to suffer from sleep problems, which have never been investigated in detail. Objective: The aim of this study is to investigate the pathogenesis of sleep disorders in patients with CS. Methods: We performed a questionnaire survey of the families of patients with CS, enzyme-linked immunosorbent analyses of the melatonin metabolite, 6-sulphatoxymelatonin (6-SM), in the patients’ urine, and immunohistochemistry in the hypothalamus, the basal nucleus of Meynert (NbM), and the pedunculopontine tegmental nucleus (PPN) in four autopsy cases. Results: Sleep–wakefulness rhythms were disturbed in patients with CS, and these disturbances seemed to be related to a reduced urinary excretion of 6-SM. In addition, although the hypothalamic nuclei were comparatively preserved, acetylcholine neurons (AchNs) were severely decreased in the NbM and PPN. Conclusions: AchNs modulate both arousal and rapid eye movement sleep, and selective lesions of AchNs in the PPN and/or NbM in combination with disturbed melatonin metabolism might be involved in the sleep disorders in CS.