Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome

doi:10.1067/mpd.2001.115018

The Journal of Pediatrics

Volume 139, Issue 1, July 2001, Pages 111-116

https://doi.org/10.1067/mpd.2001.115018 Get rights and content

Abstract

Objective: The objective was to determine the circadian rhythm of melatonin in the Smith-Magenis syndrome (SMS), which causes behavioral problems and sleep disturbance. Study design: Questionnaires, sleep consultations, and sleep diaries were obtained in 20 children with SMS (9 girls, 11 boys aged 4 to 17 years). Actigraphy, electroencephalography, and the circadian variations of plasma melatonin, cortisol, and growth hormone were recorded in 8 patients. Early sleep onset, early sleep offset, and sleep attack indicated sleep disturbance. Results: All children with SMS had a phase shift of their circadian rhythm of melatonin. Time at onset of melatonin secretion was 6 AM ± 2 (control group: 9 P.M. ± 2). Peak time was 12 PM ± 1 (control group: 3:30 AM ± 1:30), and melatonin offset was at 8 PM ± 1 (control group: 6 AM ± 1). Behavioral problems correlated with the inverted circadian rhythm of melatonin. Conclusion: Considering that clock genes mediate the generation of circadian rhythms, we suggest that haploinsufficiency for a circadian system gene mapping to chromosome 17p11.2 may cause the inversion of the circadian rhythm of melatonin in SMS. (J Pediatr 2001;139:111-6)

Section snippets

PATIENTS AND METHODS

A total of 20 children with SMS (9 girls, 11 boys) aged 4 to 17 years were included in the study. Inclusion criteria were (1) typical behavioral and dysmorphic features and (2) cytogenetic and fluorescence in situ hybridization analysis evidence of chromosome 17p11.2 deletion with an ONCOR probe (D17S258). Questionnaires and sleep diaries were sent to parents and filled out at home over a period of 1 month. The age-matched control group consisted of children and adolescents recruited in a

RESULTS

Questionnaires, sleep consultations, and sleep diaries revealed sleep disturbance in all 20 subjects with SMS. These symptoms had a major impact on the children with SMS and their families. All children went to bed easily after a short bedtime ritual. Bedtime was similar at 8 to 9 PM regardless of age and sex (4 through 17 years, control group aged <6 years = 7:30 to 9 PM , control group aged 7 to 13 years = 8:30 to 10 PM , control group aged 14 to 17 years = 9:30 to 11:30 PM ; see Table).

Table.

DISCUSSION

This study reports severe sleep disturbance and phase shift of the circadian rhythm of melatonin in a series of children with SMS. Similar findings on disturbed sleep pattern and urinary excretion of 6 sulphatoxymelatonin have been reported.¹⁰ Early sleep onset, frequent awakenings, and early sleep offset were consistent features of the disease and are highly specific diagnostic criteria in SMS. “Sleep attacks” occurring at the end of the day may represent the endogenous sleep onset of the

Acknowledgements

We thank the children, parents, and the ASMS 17 family support group of France for participating in this study, F. Salefranque, J. Brun, R. Brauner for helpful cooperation. Part of this study has been supported by a Blomed grant (BMH4 CT 97 2327).

References (25)

U Albrecht et al.
A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light
Cell
(1997)
L Potocki et al.
Subunit 3 of the COP9 signal transduction complex is conserved from plants to humans and maps within the Smith-Magenis syndrome critical region in 17p11.2
Genomics
(1999)
RC Juyal et al.
Molecular analysis of 17p11.2 deletion in 62 Smith-Magenis syndrome patients
Am J Med Genet
(1996)
ACM Smith et al.
Interstitial deletion of 17p11.2 in nine patients
Am J Med Genet
(1986)
A Moncla et al.
Physical mapping of microdeletions of the chromosome 17 short arm associated with Smith-Magenis syndrome
Hum Genet
(1993)
F Greenberg et al.
Multi disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)
Am J Med Genet
(1996)
ACM Smith et al.
Behavioral phenotype of SmithMagenis syndrome (del 17p11.2)
Am J Med Genet
(1998)
ACM Smith et al.
Sleep disturbance in Smith-Magenis syndrome (del 17p11.2)
Am J Med Genet
(1998)
L Potocki et al.
Twenty-four how urinary excretion of 6-sulphatoxymelatonin in Smith-Magenis syndrome
American College of Medical Genetics Conference
(1997)
A. Cavallo
Plasma melatonin rhythm in normal puberty: interactions of age and pubertal stages
Neuroendocrinology
(1992)

J Brun et al.

Night/day variations and daily excretion of melatonin and 6-sulfatoxymelatonin from infancy to adulthood

Exp Clin Endrocrinol

(1992)

L Potocki et al.

Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome

J Med Genet

(2000)

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^☆: Supported in part by a Blomed grant (BMH4 CT 97 2327).

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Original articlesInversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome☆

Abstract

Section snippets

PATIENTS AND METHODS

RESULTS

DISCUSSION

Acknowledgements

Cell

Genomics

Molecular analysis of 17p11.2 deletion in 62 Smith-Magenis syndrome patients

Am J Med Genet

Interstitial deletion of 17p11.2 in nine patients

Am J Med Genet

Physical mapping of microdeletions of the chromosome 17 short arm associated with Smith-Magenis syndrome

Hum Genet

Multi disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)

Am J Med Genet

Behavioral phenotype of SmithMagenis syndrome (del 17p11.2)

Am J Med Genet

Sleep disturbance in Smith-Magenis syndrome (del 17p11.2)

Am J Med Genet

Twenty-four how urinary excretion of 6-sulphatoxymelatonin in Smith-Magenis syndrome

American College of Medical Genetics Conference

Plasma melatonin rhythm in normal puberty: interactions of age and pubertal stages

Neuroendocrinology

Night/day variations and daily excretion of melatonin and 6-sulfatoxymelatonin from infancy to adulthood

Exp Clin Endrocrinol

Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome

J Med Genet

Original articles
Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome☆