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Re: Improvement of sleep disturbances and behaviour in Smith-Magenis syndrome with morning melatonin

Dear Editor

Smith-Magenis syndrome is a genetic syndrome associated with interstitial deletions of chromosome 17p11.2. Main features include congenital anomalies, abnormal behaviour and sleep/wake rhythm abnormalities.[1] The latter have been shown to result from a reversed circadian rhythm of melatonin.[2,3] Normally, secretion of melatonin peaks at night and is minimal during the day. In Smith-Magenis syndrome melatonin reaches a peak in the daytime and is lowest during the night.[2,3] This results in early onset and offset of sleep, frequent waking during the night and hypersomnia during the day.[1]

The inversion of the circadian rhythm of melatonin in Smith-Magenis syndrome can be considered as an extremely advanced or an extremely delayed melatonin rhythm. The therapeutic consequences differ: melatonin rhythm can maximally be delayed with exogenous melatonin administered 10 hours after endogenous melatonin onset and maximally be advanced by exogenous melatonin administered 5 hours before endogenous melatonin onset.[4] We hypothesised that sleep disturbances in Smith-Magenis syndrome result from an extremely advanced melatonin rhythm. Consequently, we treated a patient with Smith-Magenis syndrome with melatonin, administered after endogenous melatonin onset.

Case report
A boy with Smith-Magenis syndrome was referred to our outpatient clinic at age eight years. He had been diagnosed with the syndrome at age three years, after evaluation for developmental delay. The diagnosis had been confirmed by demonstration of a 17p11.2 deletion by FISH analysis. At the time of referral, the boy¡¦s parents reported serious disturbances of both sleep and behaviour. Mean onset of sleep was at 7.30 pm, with mean waking at 4.30 am. Moreover, there was frequent nocturnal waking and need for naps during the day. The main behavioural symptoms experienced were hyperactivity and tantrums. Because of this uncontrollable behaviour, the boy had been institutionalised. The boy was treated with a morning regimen of melatonin alone. Initially, melatonin 3 mg was administered at 4 am. Over the next weeks, the time of administration was shifted towards 7 am, and some time later to 8 am. Mean waking was delayed to 7 am, and disappearance of both night awakenings and the need for naps during the day were reported. The time of onset of sleep was not influenced by the treatment. Thus, with treatment mean gain in sleep was two-and-a-half hours. In addition, behavioural disturbances improved significantly with this treatment as well. At the time of this report, the boy has been treated with this regimen for over a year and results have been consistently positive.

Discussion
Behavioural symptoms and sleep disturbances in Smith-Magenis syndrome have a major impact on patients and their families. A therapeutic regimen using beta1-adrenergic antagonists has been reported to improve both behaviour and sleep disturbances in Smith-Magenis syndrome.[5] More recently, addition of evening melatonin suppletion to this regimen has been reported to enhance this positive effect.[6] Nine children were treated with a combination of morning acebutolol and evening melatonin, which resulted in a mean delay in sleep onset of 30 minutes and in waking by 60 minutes. The mean gain in sleep in this report was 30 minutes (rate not mentioned). The authors do not mention the considerations for administration of melatonin in the evening. Yet, evening suppletion seems logical, as by this the melatonin peak is reached at its physiological time at night.

As mentioned, we postulated that sleep disturbances in Smith-Magenis syndrome result from an extremely advanced melatonin rhythm. From the observations of the natural sleep-wake rhythm in our patient, we considered the endogenous melatonin onset to be around 7 p.m. Previous observations have shown serum melatonin peaks around this time in several other Smith-Magenis patients.[3,5,6] Consequently, we treated our patient with melatonin administered several hours after this moment, with the time of administration gradually being shifted towards a normal waking time. With this treatment, the boy¡¦s waking time shifted along with the time of administration. By this, eventual gain in sleep was two-and-a-half hours. In contrast, De Leersnijder et al. reported a mean gain in sleep of 30 minutes with melatonin and acebutolol, and no gain in sleep as much as two -and-a-half hours was reached in any of the nine children studied.[6] This suggests that a treatment regimen with morning melatonin may be more successful in restoring a normal sleep pattern in Smith-Magenis syndrome than is treatment with both a beta1-adrenergic antagonist and evening melatonin. Thus far, our observations have been limited to a single case. Yet, in our opinion the results of treatment in this case are solid and may point to a new direction in the search of adequate therapy of sleep disturbances in Smith-Magenis syndrome.

The observations in this case support our hypothesis that sleep disturbances in Smith-Magenis syndrome are due to advancement of the endogenous melatonin rhythm. The circadian disorder in Smith-Magenis syndrome may well reflect an Advanced Sleep Phase Syndrome, characterised by an advanced sleep-wake and melatonin rhythm.[7] In this syndrome, a defect in the Per2 clock gene has been demonstrated,[8] whereas in the Delayed Sleep Phase Syndrome, characterised by a delayed sleep-wake and melatonin rhythm, a defective Per3 clock gene has been found.[9] Clock genes of Smith-Magenis patients are currently under investigation and may provide further insight in the nature of the underlying sleep syndrome.

References

(1) Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J, Killian J, Murphy MA, Williamson D, Brown F, Dutton R, McCluggage C, Friedman E, Sulek M, Lupski JR. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 1996;62(3): 247-54.

(2) Potocki L, Glaze D, Tan DX, Park SS, Kashork CD, Shaffer LG, Reiter RJ, Lupski JR. Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet 2000;37:428-433.

(3) De Leersnyder H, De Blois, MC, Claustrat B, Romana S, Albrecht U, Von Kleist-Retzow JC, Delobel B, Viot G, Lyonnet S, Vekemans M, Munnich A. Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr 2001;139:111-116.

(4) Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythm according to a phase-response curve. Chronobiol Int 1992;9(5):380-392.

(5) De Leersnyder H, De Blois MC, Vekemans M, Sidi D, Villain E, Kindermans C, Munnich A. ƒÒ1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome. J Med Genet 2001;38:586-590.

(6) De Leersnyder H, Bresson JL, De Blois MC, Souberbiele JC, Mogenet A, Delhotal-Landes B, Salefranque F, Munnich A. ƒÒ1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J Med Genet 2003; 40:74-78.

(7) Wiz-Justice A, Armstrong SM. Melatonin: nature¡¦s soporific? J Sleep Res 1996; 5(2):137-141.

(8) Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001;291(5506):1040-1043.

(9) Archer NS, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, Schantz MV. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 2003;26:413-415.

Send letter to journal:
Re: Treatment of Smith-Magenis syndrome as an advanced sleep phase syndrome

Dear Editor

We read with attention and interest the eLetter by Been et al.[1] We would like to reply.

We agree with the author that Smith-Magenis syndrome (SMS) may be may be an extremely advanced sleep phase syndrome. The definition of this advanced sleep phase syndrome is based actually on clinical evaluation and melatonin dosages. A mutation of Perclock gene was found in families with familial advances sleep phase syndrome, but there is no evidence of this mutation in non familial cases and Per gene is not deleted in SMS. Following this hypothesis, it is of interest to try a treatment by melatonin in the morning to reset the melatonin secretion of this hormone in SMS. That is what the authors of the letter did, with success. Meanwhile, there is only one case studied, and they have no objective proof of the results, such as plasmatic melatonin dosages or polysomnography or actimetry recordings.

In our study, the main purpose was to act on the symptoms and to blockade the endogenous melatonin secretion to improve day behaviour (hyperactivity, tantrums, excessive daytime sleepiness) and then reset the clock by adding melatonin in the evening. Our study in 9 children is confirmed by melatonin dosages and actimetry recordings. The mechanism of melatonin phase shift in SMS is not yet known, and treatment approach acting on the mechanism as L. Bok did is very interesting and the good results he obtained encourage further studies. In the same order we could imagine using phototherapy in the morning in SMS. The difficulty is to have large series of patients of this rare disorder, and to make double-blind series if possible, with bioethical approved protocols.

Reference

(1) Been J et al. Improvement of sleep disturbances and behaviour in Smith-Magenis syndrome with morning melatonin [electronic response to de Leersnyder et al. Beta-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome] jmedgenet.com 2003 http://jmg.bmjjournals.com/cgi/eletters/40/1/74#30