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Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine logoLink to Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine
. 2019 Jul 15;15(7):1021–1029. doi: 10.5664/jcsm.7886

Sleep in ADCY5-Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements

Aurélie Méneret 1,2,*, Emmanuel Roze 1,2,*,✉, Jean-Baptiste Maranci 3, Pauline Dodet 3, Diane Doummar 4, Florence Riant 5,6, Christine Tranchant 7,8,9, Valérie Fraix 10, Mathieu Anheim 7,8,9, Asya Ekmen 2, Eavan McGovern 1, Marie Vidailhet 1,2, Isabelle Arnulf 2,3, Smaranda Leu-Semenescu 3
PMCID: PMC6622513  PMID: 31383240

Abstract

Study Objectives:

ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia.

Methods:

Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls.

Results:

We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements.

Conclusions:

In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal.

Citation:

Méneret A, Roze E, Maranci JB, Dodet P, Doummar D, Riant F, Tranchant C, Fraix V, Anheim M, Ekmen A, McGovern E, Vidailhet M, Arnulf I, Leu-Semenescu S. Sleep in ADCY5-related dyskinesia: prolonged awakenings caused by abnormal movements. J Clin Sleep Med. 2019;15(7):1021–1029.

Keywords: ADCY5, dyskinesia, chorea, dystonia, sleep

BRIEF SUMMARY

Current Knowledge/Study Rationale: Some studies reported worsening of ADCY5-related dyskinesia during sleep, a feature not usually observed in other movement disorders. We aimed to characterize sleep architecture (compared to non-medicated, healthy age and sex-matched controls) and to analyze the pattern of all movements occurring during sleep to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia.

Study Impact: We found that ADCY5-related nocturnal paroxysmal dyskinesia were not elicited by sleep or due to a primary sleep disorder. The exacerbation of paroxysmal dyskinesia upon morning awakening could be the result of an imbalance between the dopamine and adenosine pathways caused by adenylyl cyclase 5 dysfunction.

INTRODUCTION

Adenylate cyclase 5 (ADCY5) mutations cause an early-onset hyperkinetic movement disorder characterized by a variable association of dystonia, myoclonus, chorea and tremor.1,2 Clinical features also include axial hypotonia and orofacial involvement, without marked intellectual deficiency, ataxia, or epilepsy. With over 70 cases described to date, the phenotypic spectrum of ADCY5-related dyskinesia has expanded in the last few years, comprising benign hereditary chorea,3 myoclonic dystonia,4 spastic paraparesis,5 alternating hemiplegia of childhood (AHC)6 and possibly focal dystonia7 and psychiatric disorders.8 Recently, oculomotor apraxia, predominant in the vertical plane, has been described in three patients with ADCY5 mutations.9 Paroxysmal dyskinesias are also a feature of the disorder. They are usually classified according to their triggering factor (kinesigenic, non-kinesigenic, exercise-induced or nocturnal), as shown in Table 1.10,11 Paroxysmal nocturnal dyskinesia, characterized by violent attacks of dys-tonic and tonic movements occurring during sleep, is almost always a form of epilepsy called “autosomal-dominant nocturnal frontal lobe epilepsy.” Patients usually have one type of paroxysmal dyskinesia, except for those with SLC2A1 (GLUT1 deficiency) and ADCY5 mutations, who typically display various types of paroxysmal dyskinesia. In addition, patients with ADCY5 mutations may also present with nocturnal paroxysmal dyskinesia of non-epileptic origin, which is a helpful diagnostic clue.1,2,9,12–14 Their pathogenesis remains unclear. It has been proposed that drowsiness promoted dyskinesia, which could in turn dramatically delay sleep onset, while other patients reported an exacerbation of movements in the early morning.13 Electroencephalography (EEG) recordings in those patients ruled out epilepsy. Few video polysomnography (PSG) data have been published.1,9,13 Some of these abnormal movements emerged from N2 and N3 sleep, causing significant sleep disruption and poor sleep efficiency due to prolonged sleep latency associated with the presence of dyskinesia. In the most recent sleep study conducted in three patients, the authors found poor sleep efficiency due to exacerbations occurring after sleep awakening.9 These exacerbations called “ballistic bouts” (attacks of severe, generalized chorea) lasted up to 30 minutes and were more severe than diurnal episodes in two of the three patients. The ballistic bouts were triggered by disease-related myoclonic jerks, occurring in both rapid eye movement (REM) and non-REM (NREM) sleep. In some cases, clonazepam was reported to improve dyskinesia associated with disrupted sleep. Other treatments such as acetazolamide, propranolol, levetiracetam, tetrabenazine and trihexylphenidyl have shown partial and/or transient improvement in rare patients.2,3,15 A case series of three patients with ADCY5 mutations treated with deep brain stimulation after unsuccessful medication trials was reported.16 All patients had incomplete but positive responses to deep brain stimulation, with long term-efficacy that remains to be confirmed by longitudinal observation. In one patient, sleep studies identified hypoventilation as a cause of nocturnal paroxysmal episodes, with continuous positive airway pressure therapy leading to partial improvement of the nocturnal episodes.14

Table 1.

The different types of paroxysmal dyskinesias.

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To further delineate the relationship between abnormal movements and sleep in ADCY5-related dyskinesia, we performed a study in patients with ADCY5 mutations referred for sleep studies. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is a consequence of the dyskinesia.

METHODS

Patients

We enrolled 7 consecutive patients from 6 families with a proven diagnosis of ADCY5-related dyskinesia, who were referred to the sleep disorder unit by three tertiary movement disorders centers. They all complained of disturbed sleep. Sleep studies were conducted as routine tests in all these patients, who gave their approval for collecting and studying their data. In addition, they gave informed consent for publication of identifying information/images in an online open-access publication. This study is a retrospective data analysis. The anonymized data collection was approved by the national commission for data protection (CNIL - number of approval: 1975100) according to the rules of the French regulation. All patients were interviewed and examined by a neurologist and a sleep specialist at the time of the study. Patients were asked about their sleep quality, if they experienced difficulties in falling asleep or maintaining sleep, if fatigue or drowsiness promoted abnormal movements and to compare abnormal movements occurring during nighttime and daytime. Restless legs symptoms, sleepwalking, sleep terrors, confusional arousals or dream-enacting behaviors were expressly searched at the sleep interview, which was completed by the Epworth Sleepiness Scale.

Sleep Studies

Sleep monitoring included Fp1-Cz, O2-Cz, C3-A2 EEG, right and left electrooculography, electromyography (EMG; levator menti/mentalis, and bilateral tibialis anterior muscles), nasal pressure through a cannula and respiratory efforts through a thoracic and abdominal plethysmography oral thermistance, electrocardiography, pulse oximetry and infrared EEG-synchronized video-sound digitally synchronized monitoring, recording of tracheal sounds through a microphone placed at the surface of the trachea and also ambiance microphone recordings. The sleep stages, arousals, awakenings, respiratory events, periodic leg movements, and muscle activities during REM sleep were scored through visual inspection according to international criteria.17,18 An arousal was defined as an abrupt shift of EEG frequency including θ (4–7 Hz), α (8–12 Hz), or frequencies greater than 16 Hz (excluding spindles), occurring after at least 10 seconds of stable sleep and lasting 3–15 seconds. An epoch of wakefulness was defined when more than 50% of the epoch (ie, > 15 seconds) contained a background EEG α rhythm or greater. An arousal typically does not result in an awakening. Muscle activity was quantified during REM sleep using levator menti EMG. Tonic muscle activity during REM sleep was defined as prolonged muscle activity with amplitude at least equal to that observed during quiet wakefulness, lasting more than half of an epoch.17 From this finding, we calculated the percentage of REM sleep without atonia. All artifacts and increases in EMG tone due to arousals from respiratory events were excluded from the quantitative scoring of REM sleep related EMG activity.

Recordings were done without any medication, but one patient had bilateral deep brain stimulation of the internal globus pallidus. Their sleep data were compared to those of 14 nonmedicated, healthy age and sex-matched controls, who took part in various other studies.

Video PSG Abnormal Movement Analysis in Patients With ADCY5-Related Dyskinesia

Video sleep recordings were extended to 30 minutes before light extinction (A1, Figure 1) and after morning awakening (A3). Recordings exceeded 30 minutes if severe and generalized chorea was noted. The sum of all arousals/awakenings between sleep onset and final morning awakening was defined as A2 (or intra-sleep wake period). Each epoch of 30 seconds was classified with or without movement. All movements during wakefulness, all sleep stages, and nocturnal arousals/awakenings were visually analyzed by sleep specialists (IA, SLS) and movement disorder specialists (AM, PD, ER) and were classified as type 1 (a: normal, comfort movement, including turning in bed, repositioning, limb or full body movements during wakefulness/arousal; and b: physiological sleep movement, including periodic leg or arm movement, notably in N2 sleep, head jerks and twitches in REM sleep); type 2 (abnormal but not violent movement, including chorea, dyskinesia, myoclonus, myokymia, and dystonia, or head jerks or myoclonus if emerging from NREM sleep); and type 3 (abnormal, prolonged—lasting at least one epoch—and or violent, multi-focal chorea, ballistic or dystonic movements). We classified the abnormal movements (type 2 and type 3) according to the triggering factor as kinesigenic (triggered by a normal, physiological movement) or non-kinesigenic. An abnormal movement was considered to be kinesigenic if it occurred less than 5 seconds after the trigger. For intra-sleep wake periods (A2), we also differentiated abnormal movements related to a trigger emerging from sleep and abnormal movements related to a trigger that occurred while the patient was already awake. For the exacerbations of abnormal violent movements (type 3), the duration and timing related to sleep (before falling asleep, during nighttime awakenings, upon morning awakening) were analyzed. We asked whether the dystonia had been painful during the night. The referring neurologists (AM, ER) also compared the video assessments to the type and severity (duration, dynamics, violent or harmful) of involuntary movements during wakefulness.

Figure 1. Hypnogram.

Figure 1

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Difference in sleep efficacy between a patient (A) and a matched 38-year-old healthy control (B). Arrows show numerous awakenings (the sum is A2) due to abnormal movements and responsible for poor sleep efficacy in the patient (45%) compared to the control (97%) who presented only a few expected awakenings, devoid of abnormal movements. A1 = time awake before falling asleep (including 30 minutes before light extinction), A2 = total time awake after falling asleep and before waking in the morning (WASO), A3 = final awakening (time including 30 minutes of video analysis or more if presence of abnormal movements), N1 = stage N1 sleep, N2 = stage N2 sleep, N3 = stage N3 sleep, W = wake, WASO = wake after sleep onset.

Statistical Analysis

Descriptive data on sleep architecture were expressed as the median, upper and lower quartiles for quantitative variables, and numbers and percentages for qualitative variables. To compare sleep architecture between patients and controls and due to the small sample size, we used the unpaired Wilcoxon test. To test associations between movements and sleep stages/wake, we used logistic regressions: movement types were defined as dependent variables, sleep versus wake, wake periods (A1, A2 or A3), and sleep stages (N2, N3 or REM) as variables. The patient was the co-factor for all comparisons. For logistic regressions P values were presented after Bonferroni corrections. The statistical software used was R (http://www.r- project.org/).

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

RESULTS

Clinical Characteristics

The clinical and genetic characteristics of the 7 patients are shown in Table 2.

Table 2.

Clinical and genetic characteristics of the patients with ADCY5-related dyskinesia.

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All were previously reported,2 except for patient 7, who has a novel mutation (c.2081_2082insAAA/p.Lys694dup) considered to be pathogenic, as it was absent from the ExAC database, occurred de novo, and was found in a patient with a very evocative phenotype. He had an early-onset hyperkinetic movement disorder with axial hypotonia, orofacial dyskinesia, diurnal and nocturnal paroxysmal dyskinesia, without ataxia or seizures. In addition, no mutations were found in other paroxysmal dyskinesia culprit genes such as PRRT2. Difficulties in falling asleep or maintaining sleep were reported in 3 of 7 patients. The remaining four complained of overall poor quality of sleep. Only one patient (presenting with severe anxiety) considered that abnormal movements were increased during nighttime compared to daytime. One patient complained of excessive daytime sleepiness. According to patients, fatigue, but not drowsiness, promoted abnormal movements.

Sleep Studies

There were no differences between patients and controls regarding sleep time, latencies and percentages of each sleep stages, respiratory events (apnea-hypopnea index was normal), periodic leg movements index (normal in both groups) and percentage of REM sleep without atonia (Table 3). No REM sleep behavior was found, although one patient, not under any antidepressants, had a mean percentage of REM sleep without atonia of 18%, two times higher than the cutoff for REM sleep behavior disorder when scoring only the tonic activation of the mentalis muscle.19 However, he had no abnormal movement during REM sleep on video and no concomitant movement during mentalis muscle activation. In controls, the percentage of REM sleep without atonia was similar to the range reported in controls series.19

Table 3.

Sleep measures in patients with ADCY5-related dyskinesia versus healthy controls.

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Compared to healthy controls, patients had lower sleep efficiency, higher awakening index and lower arousal index.

Video PSG Abnormal Movement Analysis in Patients With ADCY5-Related Dyskinesia

A total of 3,012 epochs of wake and 5,107 epochs of sleep were analyzed. The distribution of sleep and wake epochs (number and percentages) containing movements (type 1, 2 or 3) are shown in Figure 2, Figure 3, and Figure 4. Comparative data concerning the number and percentages of triggered and non-triggered type 2 and 3 movements in wake time and different sleep stages are shown in Table S1 in the supplemental material. Episodes are shown in Video 1 and Video 2 in the supplemental material.

Figure 2. Distribution of sleep and wake epochs containing movements.

Figure 2

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Number and percentages of sleep and wake epochs containing movements type 1 (normal movements), type 2 (abnormal but not violent movements) and type 3 (abnormal prolonged and/or violent movements).

Figure 3. Distribution of wake epochs containing movements.

Figure 3

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Number and percentages of the different wake epochs (A1, A2 and A3) containing movements type 1 (normal movements), type 2 (abnormal but not violent movements) and type 3 (abnormal prolonged and/or violent movements).

Figure 4. Distribution of sleep stage epochs containing movements.

Figure 4

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Number and percentage of sleep stages epochs N1, N2, N3 and REM sleep containing movements type 1 (normal movements), type 2 (abnormal but not violent movements) and type 3 (abnormal prolonged and/or violent movements).

A decreased occurrence of all types of movements was noted when comparing sleep to wake epochs. This was observed when analyzing type 1 (physiological) movements during sleep versus wake epochs (odds ratio [OR] 0.43, 95% CI 0.19–0.49, P < .0001), as well as type 2 (OR 0.21, 95% CI 0.18–0.25, P < .0001) and type 3 (OR 0.06, 95% CI 0.04–0.08, P < .0001) abnormal movements. Moreover, this decrease was observed for both triggered (OR 0.2, CI 0.17–0.24, P < .0001) and non-triggered (OR 0.3, CI 0.23–0.38, P < .0001) type 2 movements, and also triggered (OR 0.06, CI 0.05–0.08, P < .0001) and non-triggered (OR 0.06, CI 0.03–0.11, P < .0001) type 3 movements.

We also considered the whole time between falling asleep and the final awakening (all sleep epochs plus A2 wake epochs), compared to wake periods before and after sleep (A1 plus A3). During that whole sleep time, we found a decreased occur-rence of abnormal movements type 2 (OR 0.84, CI 0.71–0.99, P = .035) and abnormal movements type 3 (OR 0.44, CI 0.37– 0.52, P < .0001). However, triggered movements type 2 were increased (OR 1.43, CI 1.13–1.79, P = .0024), but not triggered movements type 3 (OR 0.44, CI 0.36–0.53, P < .0001). When only the intra-sleep wake period (A2) was analyzed, the majority of abnormal movements were elicited by a wake-related trigger rather than one emerging from sleep (92.7% of type 2 and 64.7% of type 3 movements).

The occurrence of normal and abnormal movements was compared between the different wake periods (Table 4), and between the different sleep stages (Table 5). When movements were compared during wake before falling asleep (A1), during the night (A2) or after morning awakening (A3), the highest percentage of epochs containing normal movements was observed during the A1 period and the highest percentage of epochs containing abnormal movements was observed during the A2 period. However, the highest percentage of epochs containing abnormal movements type 2 without trigger was observed for the A3 period. Concerning sleep stages, REM sleep barely differed from N2 sleep, while the occurrence of normal and abnormal movements was notably reduced during N3 sleep compared to N2 sleep epochs. This later reduction was observed for both triggered and non-triggered abnormal movements type 2. Moreover, we observed a reduction of only non-triggered abnormal movements type 2 during N3 sleep compared to REM sleep epochs.

Table 4.

Results of logistic regressions comparing wake periods in regard to movements type 2 and type 3 with and without trigger and movements type 1 in patients with ADCY5-related dyskinesia.

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Table 5.

Results of logistic regressions comparing sleep stages in regard to movements type 2 and type 3 with and without trigger and movements type 1 in patients with ADCY5-related dyskinesia.

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The motor patterns of abnormal movements classified as type 3 (episodes of generalized chorea and ballistic attacks) were qualitatively similar during nighttime and daytime. Except for one patient without paroxysmal exacerbation, each patient had at least one paroxysmal attack during video PSG. After sleep onset and before sleep awakening, the minimal duration of one episode of paroxysmal dyskinesia was 0.5 minute and the maximal duration 5 minutes. In contrast, episodes were prolonged in the morning (eg, one patient had paroxysmal dyskinesia during 39 minutes). Two patients without a known history of parasomnia had brief confusional arousals from N3 sleep. Painful dystonia was seen after an arousal in two patients.

DISCUSSION

Our results indicate that ADCY5-related nocturnal paroxysmal dyskinesia were not due to a primary sleep disorder and were not increased during wake before falling asleep. They rather emerged after arousals and prevented patients to resume sleep immediately. Also, long and violent paroxysmal dyskinesia occurred upon morning awakening. Except for sleep efficiency and sleep measures related to the prolonged nocturnal awakenings, sleep characteristics (percent of each sleep stages, respiratory events, periodic leg movements and muscle activities) were otherwise normal in patients with ADCY5 mutations.

We found that dyskinesia were actually less common during sleep than wake when considering the whole nocturnal period, extending from 30 minutes before light extinction to 30 minutes after morning awakening. To better understand the impact of sleep on the occurrence of dyskinesia, we analyzed the whole sleep period, including sleep itself and intra-sleep wake periods. We confirmed that abnormal movements were less common during the whole sleep period when compared to wake periods before and after sleep. Moreover, the majority of abnormal movements were elicited by a wake-related trigger rather than triggers emerging from sleep.

The strengths of this study are: (1) thoroughness of the sleep study, (2) entire night video analysis by movement disorder specialists and (3) comparison of sleep architecture data to healthy subjects matched for age and sex. This study however has several limitations: (1) the relative small sample accounting for the rarity of the disorder and (2) the potential bias in movement analysis linked to the fluctuating nature of the disorder.

Movement disorders often improve during or after sleep. Dystonia and chorea fade during sleep. In some patients with Parkinson's disease, parkinsonism decreases within the first hour after morning awakening. This phenomenon known as sleep benefit is also observed in dopa-responsive dystonia. Patients with AHC and ATP1A3 mutations usually experience relief of paroxysms with sleep. Interestingly, the two cases of AHC caused by ADCY5 mutations did not report any sleep benefit.6 Worsening of motor control upon arousals has also been reported in Huntington disease, which may in part be due to underlying hypotonia, to the increase of dopamine in the morning and to the gradual change in brain connectivity occurring at sleep offset.20

Some studies reported worsening of ADCY5-related dyskinesia during sleep.2–4,6 It was hypothesized that this phenomenon was related to a dysfunction of sleep regulation itself, through a gain of function of adenylyl cyclase 5.13 Indeed, adenylyl cyclase 5 is highly expressed in the nucleus accumbens, which in animal studies is thought to control the level of cortical arousal during the sleep-wake cycle, but also to promote motor activity.21 It had been suggested that the exacerbations of dyskinesia occurred during drowsiness and could delay sleep onset while other patients reported an exacerbation of movements in the early morning.13 Our patients reported fatigue (but not drowsiness) as an exacerbating factor. Furthermore, their sleep onset latency (which corresponds to a period of intense drowsiness) was as short as that of the control group; and no abnormal (prolonged or violent) movements were observed during this period. In our study, the worst period for paroxysmal motor episodes occurred upon morning awakening, when the level of alertness was the highest. Our findings therefore do not support an association between decreased alertness and dyskinesia. In addition, there was no difference between patients and controls regarding total sleep time, which does not suggest an increased level of cortical arousal in our patients. When comparing sleep stages, an increased occurrence of abnormal movements was observed emerging from N2 sleep and REM sleep compared to N3 sleep. This was expected for N2 sleep, since this sleep stage is associated with physiological events that can trigger arousals such as limb movements or obstructive apnea/hypopnea, but unexpected for REM sleep and may have been promoted by the increased dopamine during this sleep stage. On the contrary, N3 sleep, which is under GABAergic inhibitory influence, seems protective against dyskinesia.

The hyperkinetic movements observed in both Huntington's disease and ADCY5-related dyskinesia mainly reflect GABAergic striatal medium spiny neurons dysfunction.3,22 One may speculate that these nocturnal exacerbations share similar pathogenic mechanisms that involve imbalance between the dopamine and adenosine pathways. The medium spiny neurons have two types of projection: (1) striato-pallidal neurons that express adenosine A2A receptors (A2AR) and dopamine D2 receptors, which project to the external globus pallidus (this inhibitory loop is thought to be hypoactive in Huntington's disease),23 and (2) striatonigral neurons that express adenosine A1 receptors (A1R) and dopamine D1 receptors and project primarily to the substantia nigra pars reticulata and the internal globus pallidus.24 The inhibitory role of adenosine controls the function of the striato-pallidal neurons through antagonist interactions between A2A and D2 receptors, with the formation of receptor heteromers. Interactions between A2A and D2 receptors are exerted at the level of adenylate cyclase type 5. Behavioral findings confirmed the existence of antagonistic adenosine - dopamine interactions in the brain: the stimulation of A2AR inhibits locomotion like dopamine D2 receptors antagonists.25 In addition to its inhibitory role on locomotion, adenosine also promotes sleep. It has been shown that striatal adenosine A2AR neurons have a crucial role in homeostatic sleep regulation and play a predominant role in sleep induction.26–28 Indeed, adenosine, which is released as a neuromodulator in the brain, has been proposed to act as one of the most potent endogenous substances to accumulate in the brain during wakefulness and promote physiological sleep through activation of adenosine receptors A1R or A2AR.27,29,30 In rodents, activation of A2AR neurons in the striatum induced physiological NREM sleep. The wake-promoting effect of caffeine (an antagonist of A2AR) is abolished in A2AR knockout mice, suggesting a primary effect of caffeine through A2AR.27 Some patients with ADCY5 mutation reported motor improvement with caffeine, probably through A2AR.31 Secreted with a circadian rhythm, dopamine, which stimulates adenylyl cyclase 5 through the D1 receptors and inhibits it through the D2 receptors, is high in the morning whereas adenosine, which stimulates adenylyl cyclase 5 through A2AR, is at its lowest upon awakening. A possible explanation for the exacerbation of paroxysmal dyskinesia upon morning awakening could therefore be that of an imbalance between the direct and indirect pathways caused by the altered function of adenylyl cyclase 5. Further studies, preferably in animal models, are necessary to decipher these mechanisms.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. A. Méneret received travel funding from Abbvie and honoraria for speaking at the Movement Disorders Society Congress. E. Roze received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Ultragenyx, Fondation Desmarest, AMADYS, Fonds de Dotation Brou de Laurière; has served on scientific advisory boards for Orkyn, Aguettant, Merz-Pharma; has received honoraria for speeches from Orkyn, Aguettant, Merz-Pharma, Medday-Pharma. M. Anheim received speaker honoraria and travel grants from Actelion Pharmaceuticals, Merz, UCB, AbbVie, Orkyn. E. McGovern received travel funding from Elivie. M. Vidailhet received travel funding grants from EAN and MDS. I. Arnulf had a paid speaking engagement with UCB pharma and was a consultant for Novartis. S. Leu-Semenescu had a paid speaking engagement with UCB pharma. The other authors report no conflicts of interest.

ACKNOWLEDGMENTS

The authors thank Arlette Welaratne for her help in gathering the patients consent forms and adcy5.org for support. Author contributions: conception of the research project: AM, ER and SLS. Organization and Execution of the research project: AM, ER, PD, DD, CT, VF, FR, MA, AE, EM, MV, IA, JBM and SLS. Statistical analysis: SLS and JBM. Manuscript preparation: writing of the first draft AM, ER, IA and SLS, review and critique: EM, PD, DD, CT, VF, FR, MA, AE, MV, IA, JBM.

ABBREVIATIONS

A1AR

adenosine A1A receptors

A2AR

adenosine A2A receptors

ADCY5

adenylate cyclase type 5

AHC

alternating hemiplegia of childhood

EEG

electroencephalography

EMG

electromyography

NREM

non-rapid eye movement

PSG

polysomnography

REM

rapid eye movement

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