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Cited by 126Circadian rhythm and melatoninSleep and related disordersSleep and Wakefulness Research

β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome

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De Leersnyder, H, Bresson, J L, de Blois, M-C, Souberbielle, J-C, Mogenet, A, Delhotal-Landes, B, Salefranque, F, Munnich, A·2003·Journal of Medical Genetics
DOI 10.1136/jmg.40.1.74PMC PMC1735264
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Abstract

irst 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.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 hormone 8-10 (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.Because the circadian rhythm of melatonin is controlled by the sympathetic nervous system, 11 12 SMS children were given acebutolol, as β 1 -adrenergic antagonists reduce the production of melatonin.13 14 Here, we show that the combination of morning β 1 -adrenergic antagonist and evening melatonin administration restored plasma circadian melatonin rhythm, decreased the frequency of behavioural disturbances, and enhanced sleep in SMS. METHODS PatientsTen children (six boys, four girls, aged 4-18 years) were recruited from the cohort of SMS children diagnosed at Necker-Enfants Malades Hospital, Paris.The bioethical human research committee approved the investigation protocol and the parents signed an informed consent form before inclusion in the study.All SMS patients met the inclusion clinical criteria, namely: facial dysmorphism, developmental delay, speech delay, hyperactivity, attention deficit, and sleep disturbances.All carried a 17p11-2 deletion confirmed by

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  • Combining β1-adrenergic receptor antagonism with timed administration of exogenous melatonin greatly improves sleep and also reduces disruptive behaviours during the daytime in children and adolescents with SMS.

    “Combining β1-adrenergic receptor antagonism with timed administration of exogenous melatonin greatly improves sleep (that is, leading to fewer sleep awakenings and better organized sleep stages) and also reduces disruptive behaviours during the daytime in children and adolescents with SMS137.”

    From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [137]

  • Therapies targeting the reversal of melatonin rhythms in patients with SMS may improve sleep, as well as behaviour, attention and learning.

    “Thus, therapies targeting the reversal of melatonin rhythms in patients with SMS may improve sleep, as well as behaviour, attention and learning137–139.”

    From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [137]

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Research works printed but not linked: 9

  1. Smith ACM, McGavran L, Robinson J, Waldstein G, Macfarlane J, Zonona J, Reiss J. Interstitial deletion of 17p11.2 in nine patients. Am J Med Genet 1986;24:393-414.
  2. Greenberg F, Lewis RA, Potocki L, Potocki L, Glaze D, Parke J, Killian J, Murphy MA, Williamson D, Brown F, Dutton R, McCluggage C, Friedman E, Sulek M, Lupski JR. Multidisciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 1996;62:247-54.
  3. Smith ACM, Dykens E, Greenberg F. Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2). Am J Med Genet 1998;81:179-85.
  4. Juyal RC, Figuera LE, Hauge X, Elsea SH, Lupski JR, Greenberg F, Baldini A, Patel PI. Molecular analysis of 17p11.2 deletion in 62 Smith-Magenis syndrome patients. Am J Med Genet 1996;58:998-1007.
  5. Smith ACM, Dykens E, Greenberg F. Sleep disturbance in Smith-Magenis syndrome (del 17p11.2). Am J Med Genet 1998;81:186-91.
  6. Potocki L, Reiter RJ, Glaze D, Lupski JR. Twenty-four hours urinary excretion of 6-sulphatoxymelatonin in Smith-Magenis syndrome. American College of Medical Genetics Conference 1997:A31.
  7. Cowen PJ ; Bevan JS, Gosden B, Elliott SA. Treatment with β-adrenoreceptor blockers reduces plasma melatonin concentration. Br J Clin Pharmacol 1985;19:258-60.
  8. Jan JE, Freeman RD, Fast DK. Melatonin treatment of sleep-wake disorders in children and adolescents. Dev Med Child Neurol 1999;41:491-500.
  9. Arendt J. Mammalian pineal rhythms. Pineal Res Rev 1985;3:161-213.

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Authors
De Leersnyder, H., Bresson, J. L., de Blois, M.-C., Souberbielle, J.-C., Mogenet, A., Delhotal-Landes, B., Salefranque, F., & Munnich, A.
Affiliations
  • Hôpital Necker-Enfants Malades (FR)
  • Hôpital Ambroise-Paré (FR)
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2003-01
Volume
40
Issue
1
Pages
74-78
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmg.40.1.74
PMC
PMC1735264
OpenAlex
W2155779519
Cited by
126
References
20
Citations by year
2026: 3 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 1 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 3 · 2013: 7 · 2012: 2
FWCI
2.62
Type
journal article
Language
en
Open access
Locations
  • Journal of Medical Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Servier
  • Institut de Recherches Servier
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Keywords
Smith-Magenis syndrome, melatonin, circadian rhythm, sleep disorders, sleep phase advance, acebutolol, behavioral problems, chromosome 17p11.2 deletion, circadian clock, children, sleep attacks, nocturnal awakenings, early waking, melatonin secretion, sympathetic nervous system
MeSH terms
Abnormalities, Multiple, Acebutolol, Adolescent, Adrenergic beta-Antagonists, Child, Child, Preschool, Circadian Rhythm, Drug Administration Schedule, Female, Humans, Male, Melatonin, Sleep, Syndrome, Cohort Studies, Receptors, Adrenergic, beta-1, Chronobiology Disorders, Adrenergic beta-1 Receptor Antagonists

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