Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome.

First described by Smith et al 1 in 1982, Smith-Magenis syndrome (SMS) is a contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Clinical features include infantile hypotonia, characteristic craniofacial appearance, brachydactyly, short stature, ocular anomalies, deep, hoarse voice, early speech delay, mental retardation, and behavioural disturbances. 3 Behavioural problems include hyperactivity, attention deficit, self-injury, temper tantrums, and major sleep disturbance. These symptoms have a major impact on the children and their families. The diagnosis is based on high resolution karyotype analysis and fluorescence in situ hybridisation (FISH). Sleep disturbances occur in all cases and are predictive of maladaptive behaviour, increased by mental retardation and cognitive delay. The specific pattern of sleep disturbance in SMS includes early sleep onset, frequent awakenings, and early waking. 7 Moreover, “sleep attacks” at the end of the day are consistent features of the disease and may represent the endogenous sleep onset of the patients. The children could therefore be regarded as having a sleep phase advance. Normally, melatonin secretion increases soon after onset of darkness, peaks at midnight, and gradually falls during the second half of the night. Interestingly, all SMS patients display a phase shift of their circadian rhythm of melatonin, with a diurnal secretion of the hormone (fig 1). Tantrums and tiredness occur when melatonin rises in the morning and children have naps and sleep attacks when melatonin peaks at midday and in the evening. Sleep is fragmented with prolonged nocturnal awakenings and early waking when melatonin is low during the night (fig 1). This clinical and biological sleep phase advance supports the existence of an aberrant biological clock in SMS. Because the circadian rhythm of melatonin is controlled by the sympathetic nervous system, 12 SMS children were given acebutolol, as β1-adrenergic antagonists reduce the production of melatonin. 14 Here, we show that the combination of morning β1-adrenergic antagonist and evening melatonin administration restored plasma circadian melatonin rhythm, decreased the frequency of behavioural disturbances, and enhanced sleep in SMS.