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β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome
  1. H De Leersnyder1,
  2. J L Bresson2,
  3. M-C de Blois1,
  4. J-C Souberbielle3,
  5. A Mogenet2,
  6. B Delhotal-Landes4,
  7. F Salefranque2,
  8. A Munnich1
  1. 1Department of Genetics and Unit INSERM 393, Hôf.pital Necker Enfants-Malades, 149 rue de Sevres, 75743 Paris Cedex 15, France
  2. 2Department of Paediatrics, Hôf.pital Necker Enfants-Malades, 149 rue de Sevres, 75743 Paris Cedex 15, France
  3. 3Department of Biology, Hôf.pital Necker Enfants-Malades, 149 rue de Sevres, 75743 Paris Cedex 15, France
  4. 4Department of Toxicology, Hôf.pital Ambroise Paré, Paris, France
  1. Correspondence to:
 Professor A Munnich, Département de Génétique et Unité INSERM 393, Hôf.pital Necker Enfants-Malades, 149 rue de Sévres, 75743 Paris Cedex 15, France;

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First described by Smith et al1 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.2,3 Behavioural problems include hyperactivity, attention deficit, self-injury, temper tantrums, and major sleep disturbance.4 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).5

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.6,7 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 hormone8–10 (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.

Figure 1

(A) Inversion of serum melatonin rhythm in SMS (solid lines) as compared to age matched controls (dotted lines). (B) Sleep-wake patterns correlated with melatonin …

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