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.
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.