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Phase advance of circadian rhythms in Smith–Magenis syndrome: A case study in an adult man
Neuroscience Letters 585 (2015) 144–148
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Short communication
Phase advance of circadian rhythms in Smith–Magenis syndrome: A case study in an adult man Laurence Kocher a,d,∗ , Jocelyne Brun b , Franc¸oise Devillard c , Eric Azabou a,e , Bruno Claustrat b,f a
Service d’Explorations Fonctionnelles Neurologiques, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France Service d’Hormonologie, Centre Hospitalier Est, Hospices Civils de Lyon, France c Département de Génétique et Procréation, Centre Hospitalier Universitaire, Grenoble, France d INSERM U628, Physiologie intégrée du Système d’éveil, Domaine Rockefeller, 69008 Lyon, France e Département de Physiologie-Explorations Fonctionnelles, Hôpital Raymond-Poincaré, AP-HP, Université de Versailles Saint Quentin-En-Yvelines, 92380 Garches, France f INSERM U846, Institut Cellule Souche et Cerveau, Neurobiologie des Rythmes Circadiens et du Sommeil, 18 avenue du Doyen Lépine 69500 Bron, France b
h i g h l i g h t s • • • • •
An adult with Smith–Magenis syndrome displayed a phenotype of phase-advance. Sleep–wake cycle was phase-advanced. The plasma melatonin profile was reversed. Core body temperature displayed a phased-advance acrophase. The plasma cortisol profile showed a phased-advance acrophase.
a r t i c l e
i n f o
Article history: Received 9 July 2014 Received in revised form 17 November 2014 Accepted 25 November 2014 Available online 27 November 2014 Keywords: Smith–Magenis syndrome Circadian rhythms Temperature Melatonin Cortisol
a b s t r a c t Melatonin secretion is usually increased during the daytime and decreased at night in Smith–Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24 h profiles of core temperature, sleep–wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy-melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase-advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy-melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Smith–Magenis syndrome (SMS) is a congenital syndrome associated with a deletion of chromosome 17 band p11.2 (including
∗ Corresponding author at: Explorations Fonctionnelles et Consultations Neurologiques, bâtiment médical, 2ième étage, Centre Hospitalier Lyon-Sud 69495, Pierre-Bénite cedex, France. Tel.: +33 478861793; fax: +33 478863332. E-mail address: [email protected] (L. Kocher). http://dx.doi.org/10.1016/j.neulet.2014.11.038 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
the RAI1 gene) or a mutation in the RAI1 gene. The prevalence of the syndrome is estimated to be one in 25,000 live births [1]. All cases occur de novo. Clinically, this syndrome is characterised by craniofacial anomalies (brachycephaly with midface hypoplasia, characteristic mouth with a cupid’s bow’shape, prognathism), short stature and scoliosis, brachydactyly, ocular anomalies (myopia and strabismus, iris anomalies), developmental delay, mental retardation and abnormal behaviour such as hyperactivity, stereotypies, attention deficit and self-injury. Sleep disturbances have also been described, including early sleep onset, nocturnal awakenings, early
L. Kocher et al. / Neuroscience Letters 585 (2015) 144–148
waking and daytime sleepiness with a need for daytime naps [2–4]. 24 h polysomnography, correlated with actimetric recordings and sleep diaries, reveal a reduced total sleep time in about half of patients. Stages 3–4 non rapid eye movement sleep is reduced as well as rapid eye movement sleep [3,5]. Patients with SMS display the phenotype of an advanced sleep–wake cycle syndrome, with a tendency to sleep at daytime and be awake at night time [1,3,6,7]. Sleep alteration in SMS could be related to a disturbance of the circadian system. Normally, melatonin secretion increases soon after onset of darkness, peaks at midnight and gradually falls during the second half of the night. Usually, in SMS, melatonin rhythm begins early in the morning and peaks around noon [3,4,6,7]. However, serum cortisol and prolactin follow a normal circadian pattern, which is not in agreement with an alteration of the circadian clock [8]. Boudreau et al. [9] reported a case of a patient with normal melatonin rhythm in combination with disrupted sleep patterns. Therefore, disrupted sleep patterns cannot be attributed to the consequence of abnormal melatonin rhythm. As far, as we know, core
145
body temperature rhythm has never been reported in SMS, but can be considered as the most reliable marker of the clock activity in the presence of abnormal melatonin rhythm. Indeed, the reverse melatonin profile can be the consequence of an abnormality of the melatonin biosynthesis pathway or regulation, especially in the sympathetic system. We report here on the case of a SMS adult who was referred to the Sleep Unit for sleep evaluation and determination of his circadian profile including core temperature, 24 h blood hormone patterns and actigraphy. 2. Methods 2.1. Subject The patient (Gil. A.) was a 31-year-old man with cytogenetically confirmed SMS. The diagnosis which had only been established 2 years earlier was based on clinical features and confirmed by highresolution karyotype with detectable deletion of 17p11.2 and by
Fig. 1. Patient’s actimetry (day display). Timebase, 0.5 min, abscissa, time of the day.
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Fig. 2. Patient’s hypnogram: clock time plotted on the x-axis versus sleep stage on the y-axis taken from overnight polysomnography.
fluorescence in situ hybridization (FISH) probe specific for SMS. He was not aggressive in the morning as is typical of this condition. Due to behavioural disturbances, the subject was prescribed risperidone (1 mg twice a day). This medication was not discontinued during the study for ethical reasons.
data (zero amplitude test) were calculated to examine the appropriateness of the Cosinor model. 3. Results Overall, the patient displayed a phenotype of phase-advance.
2.2. Sleep evaluation 3.1. Actigraphy (Fig. 1) Wrist actigraphy and polysomnography were used to evaluate sleep disturbances. The subject wore an activity monitor (Actiwatch® ) for 2 weeks in his home setting. The activity monitor is a wristwatch-sized instrument that contains an accelerometer and provides an objective measure of motor activity, which allows indirect assessment of sleep/wake patterns. Sleep onsets, sleep offsets and sleep efficiency were calculated automatically using the Actiwatch® software following manual entry of estimated onset and offsets. The data were expressed graphically as actigrams. Activity recorded during the sleep period was sed for sleep efficiency calculations. The 24 h polysomnography was performed at the sleep unit, using eight channels of electroencephalography (EEG) (Fp2-C4; C4-T4; T4-O2; FP1-C3; C3-T3; T3 O1; Fz-Cz; Cz- Pz) recorded from surface electrodes placed according to the 10–20 international system. To score sleep stages as recommended by Rechtschaffen and Kales, Fp2-A1 and Fp1-A1 were also analysed after recordings. In addition to the EEG, polygraphy included two channels of electro-oculogram, three channels of electromyogram (EMG) covering sub mental, right and left leg musculature, one channel of electrocardiogram. The polysomnography data was analysed for sleep efficiency, latency to sleep onset, REM latency, and percentage of time spent in each sleep stage. 2.3. Determination of 24 h hormone and temperature profiles and data analysis In another 24 h session, blood samples (5 ml) were collected in dim light every hour for 24 h with an indwelling catheter inserted into an antecubital vein. After blood centrifugation, plasma was decanted and frozen at −20 ◦ C. Until assayed; plasma melatonin and cortisol concentrations were determined according to methods previously described [10,11]. Additionally, 6 sulfatoxymelatonin (aMT6S), the main hepatic melatonin metabolite was determined in plasma and in urine [12]. Rectal temperature was recorded every minute using an YSI® thermistor connected to a HTM 8000® monitor. Data were averaged across 10 min intervals. Temperature maxima and minima were determined after smoothing the profiles by the moving mean method. Temperature data were analysed by the Cosinor method [13]. The programme provides the mean value (mesor) and an estimation of the amplitude (one-half the peakrough difference) and acrophase (peak time referenced to local 00:00 h) of the approximated sinusoid with a 95% confidence interval (C.I.) In each case, F statistic values and the time-dependence of
Bed time was identified as being 20:40 h and 21:45 h (median: 21:00 h), except for one evening, when the patient went to bed at midnight (). Sleep latency was evaluated between 1 and 54 min (mean 21 mn), efficiency between 55.1% and 76.5% (mean 67%). Wake-up time was usually between 06:00 h and 07:00 h (median: 6:37 h), excepted at 09:00 h for the morning which followed bedtime at midnight. 3.2. 24 h polygraphy The hypnogram is shown in Fig. 2. No nap was observed during the day. The patient slept from 20:45 h to 6:43 h however, with a long awakening between 5:06 h and 6:03 h. Efficiency was at 86.6%; there were reduced stages 3–4% (14.9%) and REM-sleep (11.2%) and REM-sleep latency was as long as 144.5 min. Night time sleep data are given in Table 1. 3.3. Hormone profiles The patient displayed a completely reversed plasma melatonin rhythm, with the onset at 05:00 h and a peak at 13:00 h (Fig. 3A), and undetectable levels between 00:00 h and 04:00 h. The plasma aMT6S profile was superimposed on the melatonin one (Fig. 3B). Table 1 Patient’s sleep data. Sleep data
Polysomnography
Sleep latency (min) TST Sleep efficiency index (%) WASO (min) (%TST) Stage 1 (min) (%TST) Stage 2 (min) (%TST) SWS (min) (%TST) REMs (min) (%TST) Number of REMs episodes REMs latency
9 518.5 85.3 80 15.4 29.5 5.7 353.5 68.2 77.5 14.9 58 11.2 6 144.5
TST = total sleep time, REMS = rapid eye movements sleep, SWS = slow wave sleep, WASO = wake after sleep onset.
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Fig. 4. Plot of clock time (x-axis) versus plasma cortisol concentration (y-axis).
Fig. 3. Plot of clock time (x-axis) versus plasma melatonin concentration (y-axis: upper part), plasma ␣MT6S (y-axis: medium); comparison between plasma melatonin and aMT6S profiles (lower part).
marker and the sleep–wake cycle and cortisol rhythm, to a less degree. The slightly earlier cortisol peak we observed could be related to a masking effect of the sleep–wake cycle on cortisol secretion, in the absence of a constant routine protocol. The plasma melatonin profile, which has been shown to be pathognomonic of SMS [3], was reversed as observed in young patients. In addition, plasma aMT6s profile was closely superimposed on the melatonin one, as observed in normal subjects [12], as well as urine melatonin and aMT6s levels whose minima were located at night. These data excluded both abnormal melatonin biotransformation and excretion. Due to behavioural disturbances, the subject received risperidone (1 mg) twice a day and this medication was not discontinued during the study for ethical reasons. This treatment is likely to have interfered with sleep architecture, as risperidone has been shown to decrease wake time, REM sleep and stage shifts [14,15]. Phase-advanced clock has been hypothesised to be a factor in the pathophysiology of SMS although a primitive alteration at the level of the clock is excluded in the absence of reverse cortisol and prolactin rhythms [8]. Melatonin receptors are present in the SCN [16] and are involved in the phase response curve (PRC) of the circadian system to exogenous melatonin [17]. Patient’s melatonin concentrations were constantly increased during the daytime, between 21 and 53 pg/ml (07:00–18:00 h) and were probably responsible for a slight decrease in temperature levels. This supports previous data showing that a low melatonin dose (10 g given intravenously which evoked physiological levels) significantly attenuated the morning increase of rectal core temperature [18]. Whereas, temperature Mesor was at the lowest limit of the 95% C.I., the main
Urine profiles confirmed plasma data, with minimum melatonin and aMT6S located between 00.00 h and 08.00 h and maximum levels during the daytime. The plasma cortisol profile showed a peak at 06:00, 3 h earlier than those in the control group (Fig. 4). 3.4. Temperature Data (Fig. 5) Cosinor analysis of the core body temperature displayed a phased-advance acrophase (:12:34 h) compared with 95% C.I. of controls (15:40–16:35 h) and decreased amplitude (A:0.30 ◦ C), outside the 95% C.I. (0.44–056 ◦ C). Mesor (36.68 ◦ C) was at the lower limit of the 95% CI (36.69–36.77 ◦ C) (10) (). 4. Discussion Our study confirms the phase advance phenotype in an adult SMS case, taking in consideration temperature as the circadian
Fig. 5. Patient’s core temperature profile(--).
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temperature alteration, however, was a phase advance. Such a phase advance may also be observed after afternoon melatonin administration. [19]. Our results confirm that changes in core body temperature are an integral part of phase shifting as induced by melatonin. Also, the PRC of the endogenous secretion to exogenous melatonin given orally or intravenously infused showed in entrained conditions that the phase advance effect following vesperal administration was more marked than the phase delay after morning administration [20,21]. The melatonin PRC was updated in further studies, especially in a study involving an ultradian light/dark cycle to avoid confounding phase shifts due to abrupt shifts of sleep/dark and light exposure [22,23]. These studies involving a short melatonin signal (obtained with a fast-release melatonin capsule orally given) showed a delay zone as marked as an advance zone. In view of the melatonin profile in SMS mimicking a constant infusion over the daytime, we suggest that the central clock displays responsiveness to physiological melatonin levels different according to the time of the day, i.e. chronaesthesia (circadian changes in the susceptibility of any biosystem to a drug) [24]. Furthermore a global chronaesthesia of the brain to melatonin probably exists, since patients usually present with tantrums in the morning and sleepiness in the late afternoon, despite similar melatonin levels at both periods. In rodents, increased aggressiveness displayed by the animals during short-days periods has been attributed to increased melatonin during this period [25,26]. In humans, melatonin displays sedative and anxiolytic effects [see [27] for review]. It could be that melatonin effects differ according to the time of the day in SMS patients. In conclusion, temperature rhythm appears a reliable marker of the phase of the clock in SMS. The inhibition of diurnal melatonin secretion by administration of beta-blockers could provide further evidence that endogenous melatonin directly influence the phase of the temperature rhythm. References [1] F. Greenberg, R.A. Lewis, L. Potocki, D. Glaza, J. Parke, J. Killian, M.A. Murphy, D. Williamson, F. Brown, R. Dutton, C. McCluggage, E. Friedman, M. Sulek, J.R. Lupski, Multidisciplinary clinical study of Smith–Magenis syndrome (deletion 17p11. 2), Am. J. Med. Genet. 62 (1996) 247–254. [2] A.C.M. Smith, E. Dykens, F. Greenberg, Sleep disturbances in Smith–Magenis syndrome (del 17 p11.2), Am. J. Med. Genet. 81 (1998) 186–189. [3] H. De Leersnyder, M.C. De Blois, B. Claustrat, S. Romana, U. Albrecht, J.C. von Kleist-Retzow, B. Delobel, G. Viot, S. Lyonnet, M. Vekemans, A. Munnich, Inversion of the circadian melatonin rhythm in Smith–Magenis syndrome, J. Pediatr. 139 (2001) 111–116. [4] P.M. Boone, R.J. Reiter, D.G. Glaze, D.X. Tan, J.R. Lupski, L. Potocki, Abnormal circadian rhythm of melatonin in Smith–Magenis syndrome patients with RAI1 point mutations, Am. J. Med. Gen. 155 (2011) 2024–2027. [5] F. Greenberg, V. Guzzetta, R. Montes de Oca-Luna, R.E. Magenis, A.C.M. Smith, S.F. Richter, I. Kondo, W.B. Dobyns, P.I. Patel, J.R. Lupski, Molecular analysis of the Smith–Magenis syndrome: a possible contiguous gene syndrome associated with del(17)(p11.2), Am. J. Hum. Genet. 49 (1991) 1207–1218. [6] L. Potocki, D. Glaze, D.X. Tan, S.S. Park, C.D. Kashork, L.G. Shaffer, R.J. Reiter, J.R. Lupski, Circadian rhythm abnormalities of melatonin in Smith–Magenis syndrome, J. Med. Genet. 37 (2000) 428–433.
[7] H. De Leersnyder, M.C. De Blois, J.L. Bresson, D. Sidi, B. Claustrat, A. Munnich, Inversion of the circadian melatonin rhythm in Smith–Magenis syndrome, Rev. Neurol. (Paris) 159 (Suppl. 6) (2003) S21–S26. [8] H. De Leersnyder, Inverted rhythm of melatonin secretion in Smith–Magenis syndrome: from symptoms to treatment, Trends Endocrinol. Metab. 17 (2006) 291–298. [9] E.A. Boudreau, K.P. Johnson, A.R. Jackman, J. Blancato, M. Huising, C. Bendavid, M. Jones, S.C. Chandrasekharappa, A.J. Lewy, A.C.M. Smith, R.E. Magenis, Review of disrupted sleep patterns in Smith–Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11. 2 deletion, Am. J. Med. Gen. Part A 149A (2009) 1382–1391. [10] J. Brun, G. Chamba, Y. Khalfallah, P. Girard, I. Boissy, H. Bastuji, G. Sassolas, B. Claustrat, Effect of modafinil on plasma melatonin cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation, J. Sleep Res. 7 (1998) 105–114. [11] C. Mallo, R. Zaidan, G. Galy, E. Vermeulen, J. Brun, G. Chazot, B. Claustrat, Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection, Eur. J. Clin. Pharmacol. 38 (1990) 297–301. [12] C. Harthé, B. Claustrat, J. Brun, G. Chazot, Direct radio immunoassay of 6 sulfatoxymelatonin in plasma with use of an iodinated trace, Clin. Chem. 37 (1991) 536–539. [13] C. Faure, C. Nemoz, B. Claustrat, A graphical and statistical method for investigation of time series in chronobiology according to the cosinor procedure, Compt. Biol. Med. 20 (1990) 319–329. [14] A.L. Sharpley, Z. Bhagwagar, S. Hafizi, W.R. Whale, H.J. Gijsman, P.J. Cowen, Risperidone augmentation decreases rapid eye movement sleep and decreases wake in treatment-resistant depressed patients, J. Clin. Psychiatry 64 (2003) 192–196. [15] S. Gimenez, S. Clos, S. Romero, E. Grasa, A. Morte, M.J. Barbanoj, Effects of olanzapine, risperidone and haloperidol on sleep after a single oral morning dose in healthy volunteers, Psychopharmacology 190 (2007) 507–516. [16] M.L. Dubocovich, Melatonin receptors: role on sleep and circadian rhythm regulation, Sleep Med. Suppl. 3 (2007) 34–42. [17] M.L. Dubocovich, K. Yun, V.V.M. Al-Ghoul, S. Benloucif, M.I. Masana, Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms, FASEB J. 12 (1998) 1211–1220. [18] C.J. Van den Heuvel, D.J. Kennaway, D. Dawson, Thermoregulatory and soporific effects of very low dose melatonin injection, Am. J. Physiol. 276 (1999) E249–54. [19] S. Deacon, J. English, J. Arendt, Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans, Neurosci. Lett. 178 (1994) 32–34. [20] A.J. Lewy, S. Ahmed, J.M. Jackson, R.L. Sack, Melatonin shifts human circadian rhythms according to a phase-response curve, Chronobiol. Int. 5 (1992) 380–392. [21] R. Zaidan, M. Geoffriau, J. Brun, J. Taillard, C. Bureau, G. Chazot, B. Claustrat, Melatonin is able to influence its secretion in humans: description of a phase-response curve, Neuroendocrinology 60 (1994) 105–112. [22] A.J. Lewy, V.K. Bauer, S. Ahmed, K.H. Thomas, N.L. Cutler, C.M. Singer, M.T. Moffit, R.L. Sack, The human phase response curve (PRC) to melatonin is about 12 h out of phase with the PRC to light, Chronobiol. Int. 15 (1998) 71–83. [23] H.J. Burgess, V.L. Revell, T.A. Molina, C.I. Eastman, Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg, J. Clin. Endocrinol. Metab. 95 (2010) 3325–3331. [24] A. Reinberg, Circadian rhythms in effects of hypnotics and sleep inducers, Int. J. Pharmacol. Res. 6 (1986) 33–44. [25] G.E. Demas, K.M. Polacek, A. Durazzo, A.M. Jasnow, Adrenal hormones mediate melatonin-induced increases in aggression in male siberian hamsters (Phodopus sungorus), Horm. Behav. 46 (2004) 582–591. [26] A.M. Jasnow, K.L. Huhman, T.J. Bartness, G.E. Demas, Short days and exogenous melatonin increase aggression of male syrian hamsters (Mesocricetus auratus), Horm. Behav. 42 (2002) 13–20. [27] E.R. Rios, E.T. Venancio, N.F. Rocha, D.J. Woods, S. Vasconcelos, D. Macedo, F.C. Sousa, M.M. Fonteles, Melatonin: pharmacological aspects and clinical trends, Int. J. Neurosci. 120 (2010) 583–589.
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Short communication
Phase advance of circadian rhythms in Smith–Magenis syndrome: A case study in an adult man Laurence Kocher a,d,∗ , Jocelyne Brun b , Franc¸oise Devillard c , Eric Azabou a,e , Bruno Claustrat b,f a
Service d’Explorations Fonctionnelles Neurologiques, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France Service d’Hormonologie, Centre Hospitalier Est, Hospices Civils de Lyon, France c Département de Génétique et Procréation, Centre Hospitalier Universitaire, Grenoble, France d INSERM U628, Physiologie intégrée du Système d’éveil, Domaine Rockefeller, 69008 Lyon, France e Département de Physiologie-Explorations Fonctionnelles, Hôpital Raymond-Poincaré, AP-HP, Université de Versailles Saint Quentin-En-Yvelines, 92380 Garches, France f INSERM U846, Institut Cellule Souche et Cerveau, Neurobiologie des Rythmes Circadiens et du Sommeil, 18 avenue du Doyen Lépine 69500 Bron, France b
h i g h l i g h t s • • • • •
An adult with Smith–Magenis syndrome displayed a phenotype of phase-advance. Sleep–wake cycle was phase-advanced. The plasma melatonin profile was reversed. Core body temperature displayed a phased-advance acrophase. The plasma cortisol profile showed a phased-advance acrophase.
a r t i c l e
i n f o
Article history: Received 9 July 2014 Received in revised form 17 November 2014 Accepted 25 November 2014 Available online 27 November 2014 Keywords: Smith–Magenis syndrome Circadian rhythms Temperature Melatonin Cortisol
a b s t r a c t Melatonin secretion is usually increased during the daytime and decreased at night in Smith–Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24 h profiles of core temperature, sleep–wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy-melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase-advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy-melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Smith–Magenis syndrome (SMS) is a congenital syndrome associated with a deletion of chromosome 17 band p11.2 (including
∗ Corresponding author at: Explorations Fonctionnelles et Consultations Neurologiques, bâtiment médical, 2ième étage, Centre Hospitalier Lyon-Sud 69495, Pierre-Bénite cedex, France. Tel.: +33 478861793; fax: +33 478863332. E-mail address: [email protected] (L. Kocher). http://dx.doi.org/10.1016/j.neulet.2014.11.038 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
the RAI1 gene) or a mutation in the RAI1 gene. The prevalence of the syndrome is estimated to be one in 25,000 live births [1]. All cases occur de novo. Clinically, this syndrome is characterised by craniofacial anomalies (brachycephaly with midface hypoplasia, characteristic mouth with a cupid’s bow’shape, prognathism), short stature and scoliosis, brachydactyly, ocular anomalies (myopia and strabismus, iris anomalies), developmental delay, mental retardation and abnormal behaviour such as hyperactivity, stereotypies, attention deficit and self-injury. Sleep disturbances have also been described, including early sleep onset, nocturnal awakenings, early
L. Kocher et al. / Neuroscience Letters 585 (2015) 144–148
waking and daytime sleepiness with a need for daytime naps [2–4]. 24 h polysomnography, correlated with actimetric recordings and sleep diaries, reveal a reduced total sleep time in about half of patients. Stages 3–4 non rapid eye movement sleep is reduced as well as rapid eye movement sleep [3,5]. Patients with SMS display the phenotype of an advanced sleep–wake cycle syndrome, with a tendency to sleep at daytime and be awake at night time [1,3,6,7]. Sleep alteration in SMS could be related to a disturbance of the circadian system. Normally, melatonin secretion increases soon after onset of darkness, peaks at midnight and gradually falls during the second half of the night. Usually, in SMS, melatonin rhythm begins early in the morning and peaks around noon [3,4,6,7]. However, serum cortisol and prolactin follow a normal circadian pattern, which is not in agreement with an alteration of the circadian clock [8]. Boudreau et al. [9] reported a case of a patient with normal melatonin rhythm in combination with disrupted sleep patterns. Therefore, disrupted sleep patterns cannot be attributed to the consequence of abnormal melatonin rhythm. As far, as we know, core
145
body temperature rhythm has never been reported in SMS, but can be considered as the most reliable marker of the clock activity in the presence of abnormal melatonin rhythm. Indeed, the reverse melatonin profile can be the consequence of an abnormality of the melatonin biosynthesis pathway or regulation, especially in the sympathetic system. We report here on the case of a SMS adult who was referred to the Sleep Unit for sleep evaluation and determination of his circadian profile including core temperature, 24 h blood hormone patterns and actigraphy. 2. Methods 2.1. Subject The patient (Gil. A.) was a 31-year-old man with cytogenetically confirmed SMS. The diagnosis which had only been established 2 years earlier was based on clinical features and confirmed by highresolution karyotype with detectable deletion of 17p11.2 and by
Fig. 1. Patient’s actimetry (day display). Timebase, 0.5 min, abscissa, time of the day.
146
L. Kocher et al. / Neuroscience Letters 585 (2015) 144–148
Fig. 2. Patient’s hypnogram: clock time plotted on the x-axis versus sleep stage on the y-axis taken from overnight polysomnography.
fluorescence in situ hybridization (FISH) probe specific for SMS. He was not aggressive in the morning as is typical of this condition. Due to behavioural disturbances, the subject was prescribed risperidone (1 mg twice a day). This medication was not discontinued during the study for ethical reasons.
data (zero amplitude test) were calculated to examine the appropriateness of the Cosinor model. 3. Results Overall, the patient displayed a phenotype of phase-advance.
2.2. Sleep evaluation 3.1. Actigraphy (Fig. 1) Wrist actigraphy and polysomnography were used to evaluate sleep disturbances. The subject wore an activity monitor (Actiwatch® ) for 2 weeks in his home setting. The activity monitor is a wristwatch-sized instrument that contains an accelerometer and provides an objective measure of motor activity, which allows indirect assessment of sleep/wake patterns. Sleep onsets, sleep offsets and sleep efficiency were calculated automatically using the Actiwatch® software following manual entry of estimated onset and offsets. The data were expressed graphically as actigrams. Activity recorded during the sleep period was sed for sleep efficiency calculations. The 24 h polysomnography was performed at the sleep unit, using eight channels of electroencephalography (EEG) (Fp2-C4; C4-T4; T4-O2; FP1-C3; C3-T3; T3 O1; Fz-Cz; Cz- Pz) recorded from surface electrodes placed according to the 10–20 international system. To score sleep stages as recommended by Rechtschaffen and Kales, Fp2-A1 and Fp1-A1 were also analysed after recordings. In addition to the EEG, polygraphy included two channels of electro-oculogram, three channels of electromyogram (EMG) covering sub mental, right and left leg musculature, one channel of electrocardiogram. The polysomnography data was analysed for sleep efficiency, latency to sleep onset, REM latency, and percentage of time spent in each sleep stage. 2.3. Determination of 24 h hormone and temperature profiles and data analysis In another 24 h session, blood samples (5 ml) were collected in dim light every hour for 24 h with an indwelling catheter inserted into an antecubital vein. After blood centrifugation, plasma was decanted and frozen at −20 ◦ C. Until assayed; plasma melatonin and cortisol concentrations were determined according to methods previously described [10,11]. Additionally, 6 sulfatoxymelatonin (aMT6S), the main hepatic melatonin metabolite was determined in plasma and in urine [12]. Rectal temperature was recorded every minute using an YSI® thermistor connected to a HTM 8000® monitor. Data were averaged across 10 min intervals. Temperature maxima and minima were determined after smoothing the profiles by the moving mean method. Temperature data were analysed by the Cosinor method [13]. The programme provides the mean value (mesor) and an estimation of the amplitude (one-half the peakrough difference) and acrophase (peak time referenced to local 00:00 h) of the approximated sinusoid with a 95% confidence interval (C.I.) In each case, F statistic values and the time-dependence of
Bed time was identified as being 20:40 h and 21:45 h (median: 21:00 h), except for one evening, when the patient went to bed at midnight (). Sleep latency was evaluated between 1 and 54 min (mean 21 mn), efficiency between 55.1% and 76.5% (mean 67%). Wake-up time was usually between 06:00 h and 07:00 h (median: 6:37 h), excepted at 09:00 h for the morning which followed bedtime at midnight. 3.2. 24 h polygraphy The hypnogram is shown in Fig. 2. No nap was observed during the day. The patient slept from 20:45 h to 6:43 h however, with a long awakening between 5:06 h and 6:03 h. Efficiency was at 86.6%; there were reduced stages 3–4% (14.9%) and REM-sleep (11.2%) and REM-sleep latency was as long as 144.5 min. Night time sleep data are given in Table 1. 3.3. Hormone profiles The patient displayed a completely reversed plasma melatonin rhythm, with the onset at 05:00 h and a peak at 13:00 h (Fig. 3A), and undetectable levels between 00:00 h and 04:00 h. The plasma aMT6S profile was superimposed on the melatonin one (Fig. 3B). Table 1 Patient’s sleep data. Sleep data
Polysomnography
Sleep latency (min) TST Sleep efficiency index (%) WASO (min) (%TST) Stage 1 (min) (%TST) Stage 2 (min) (%TST) SWS (min) (%TST) REMs (min) (%TST) Number of REMs episodes REMs latency
9 518.5 85.3 80 15.4 29.5 5.7 353.5 68.2 77.5 14.9 58 11.2 6 144.5
TST = total sleep time, REMS = rapid eye movements sleep, SWS = slow wave sleep, WASO = wake after sleep onset.
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Fig. 4. Plot of clock time (x-axis) versus plasma cortisol concentration (y-axis).
Fig. 3. Plot of clock time (x-axis) versus plasma melatonin concentration (y-axis: upper part), plasma ␣MT6S (y-axis: medium); comparison between plasma melatonin and aMT6S profiles (lower part).
marker and the sleep–wake cycle and cortisol rhythm, to a less degree. The slightly earlier cortisol peak we observed could be related to a masking effect of the sleep–wake cycle on cortisol secretion, in the absence of a constant routine protocol. The plasma melatonin profile, which has been shown to be pathognomonic of SMS [3], was reversed as observed in young patients. In addition, plasma aMT6s profile was closely superimposed on the melatonin one, as observed in normal subjects [12], as well as urine melatonin and aMT6s levels whose minima were located at night. These data excluded both abnormal melatonin biotransformation and excretion. Due to behavioural disturbances, the subject received risperidone (1 mg) twice a day and this medication was not discontinued during the study for ethical reasons. This treatment is likely to have interfered with sleep architecture, as risperidone has been shown to decrease wake time, REM sleep and stage shifts [14,15]. Phase-advanced clock has been hypothesised to be a factor in the pathophysiology of SMS although a primitive alteration at the level of the clock is excluded in the absence of reverse cortisol and prolactin rhythms [8]. Melatonin receptors are present in the SCN [16] and are involved in the phase response curve (PRC) of the circadian system to exogenous melatonin [17]. Patient’s melatonin concentrations were constantly increased during the daytime, between 21 and 53 pg/ml (07:00–18:00 h) and were probably responsible for a slight decrease in temperature levels. This supports previous data showing that a low melatonin dose (10 g given intravenously which evoked physiological levels) significantly attenuated the morning increase of rectal core temperature [18]. Whereas, temperature Mesor was at the lowest limit of the 95% C.I., the main
Urine profiles confirmed plasma data, with minimum melatonin and aMT6S located between 00.00 h and 08.00 h and maximum levels during the daytime. The plasma cortisol profile showed a peak at 06:00, 3 h earlier than those in the control group (Fig. 4). 3.4. Temperature Data (Fig. 5) Cosinor analysis of the core body temperature displayed a phased-advance acrophase (:12:34 h) compared with 95% C.I. of controls (15:40–16:35 h) and decreased amplitude (A:0.30 ◦ C), outside the 95% C.I. (0.44–056 ◦ C). Mesor (36.68 ◦ C) was at the lower limit of the 95% CI (36.69–36.77 ◦ C) (10) (). 4. Discussion Our study confirms the phase advance phenotype in an adult SMS case, taking in consideration temperature as the circadian
Fig. 5. Patient’s core temperature profile(--).
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temperature alteration, however, was a phase advance. Such a phase advance may also be observed after afternoon melatonin administration. [19]. Our results confirm that changes in core body temperature are an integral part of phase shifting as induced by melatonin. Also, the PRC of the endogenous secretion to exogenous melatonin given orally or intravenously infused showed in entrained conditions that the phase advance effect following vesperal administration was more marked than the phase delay after morning administration [20,21]. The melatonin PRC was updated in further studies, especially in a study involving an ultradian light/dark cycle to avoid confounding phase shifts due to abrupt shifts of sleep/dark and light exposure [22,23]. These studies involving a short melatonin signal (obtained with a fast-release melatonin capsule orally given) showed a delay zone as marked as an advance zone. In view of the melatonin profile in SMS mimicking a constant infusion over the daytime, we suggest that the central clock displays responsiveness to physiological melatonin levels different according to the time of the day, i.e. chronaesthesia (circadian changes in the susceptibility of any biosystem to a drug) [24]. Furthermore a global chronaesthesia of the brain to melatonin probably exists, since patients usually present with tantrums in the morning and sleepiness in the late afternoon, despite similar melatonin levels at both periods. In rodents, increased aggressiveness displayed by the animals during short-days periods has been attributed to increased melatonin during this period [25,26]. In humans, melatonin displays sedative and anxiolytic effects [see [27] for review]. It could be that melatonin effects differ according to the time of the day in SMS patients. In conclusion, temperature rhythm appears a reliable marker of the phase of the clock in SMS. The inhibition of diurnal melatonin secretion by administration of beta-blockers could provide further evidence that endogenous melatonin directly influence the phase of the temperature rhythm. References [1] F. Greenberg, R.A. Lewis, L. Potocki, D. Glaza, J. Parke, J. Killian, M.A. Murphy, D. Williamson, F. Brown, R. Dutton, C. McCluggage, E. Friedman, M. Sulek, J.R. Lupski, Multidisciplinary clinical study of Smith–Magenis syndrome (deletion 17p11. 2), Am. J. Med. Genet. 62 (1996) 247–254. [2] A.C.M. Smith, E. Dykens, F. Greenberg, Sleep disturbances in Smith–Magenis syndrome (del 17 p11.2), Am. J. Med. Genet. 81 (1998) 186–189. [3] H. De Leersnyder, M.C. De Blois, B. Claustrat, S. Romana, U. Albrecht, J.C. von Kleist-Retzow, B. Delobel, G. Viot, S. Lyonnet, M. Vekemans, A. Munnich, Inversion of the circadian melatonin rhythm in Smith–Magenis syndrome, J. Pediatr. 139 (2001) 111–116. [4] P.M. Boone, R.J. Reiter, D.G. Glaze, D.X. Tan, J.R. Lupski, L. Potocki, Abnormal circadian rhythm of melatonin in Smith–Magenis syndrome patients with RAI1 point mutations, Am. J. Med. Gen. 155 (2011) 2024–2027. [5] F. Greenberg, V. Guzzetta, R. Montes de Oca-Luna, R.E. Magenis, A.C.M. Smith, S.F. Richter, I. Kondo, W.B. Dobyns, P.I. Patel, J.R. Lupski, Molecular analysis of the Smith–Magenis syndrome: a possible contiguous gene syndrome associated with del(17)(p11.2), Am. J. Hum. Genet. 49 (1991) 1207–1218. [6] L. Potocki, D. Glaze, D.X. Tan, S.S. Park, C.D. Kashork, L.G. Shaffer, R.J. Reiter, J.R. Lupski, Circadian rhythm abnormalities of melatonin in Smith–Magenis syndrome, J. Med. Genet. 37 (2000) 428–433.
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