Clinical reviewSleep disorders and Parkinson disease; lessons from genetics
Introduction
As the world's population ages, age-related disorders such as Parkinson disease (PD) threaten to become a significant financial and social burden [1], on top of the personal burden carried by the affected individuals and their families. PD is the most common neurodegenerative movement disorder, affecting 1–2% of the population older than 60 y [2], [3], [4], and the projected number of PD patients in 2030 in 15 of the most populous nations is estimated to be 8.67 million patients [5]. PD is pathologically characterized by degeneration of the substantia nigra (SN) and the presence of Lewy bodies, which are aggregates of various proteins, primarily α-synuclein [6]. As such, it is part of a family of disorders collectively termed synucleinopathies, mainly including PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [7]. Other diseases may also have α-synuclein depositions, and while this is a shared feature, it does not imply that α-synuclein is the sole cause for these disorders.
The pathogenic process leading to PD begins many years before diagnosis, which is traditionally based on classical motor symptoms; therefore, the course of PD can be divided accordingly, to preclinical PD, prodromal PD (non-motor PD) and clinical PD, when motor symptoms appear [8]. This recent division aims to distinguish between the different phases of PD, first, when neurodegeneration started but no symptoms are present (preclinical PD), then when early symptoms appear but PD is not diagnosed yet (prodromal PD), and lastly when motor symptoms present (clinical PD) [8]. Clinical PD occurs when about half of the dopaminergic neurons in the SN had already been irreversibly degenerated and died, and the typical motor symptoms appear [9]. One of the main challenges in PD research is identifying individuals during the prodromal phase of PD; when neuroprotective therapy is available, early diagnosis of PD will be crucial to slow or stop the degenerative process prior to motor parkinsonism.
Sleep-related disorders are, as a group, the most common non-motor features of PD. Insomnia, fragmentation of sleep, and excessive daytime sleepiness (EDS) are experienced by more than 50% of PD patients in some studies [10], [11]. During the prodromal phase of PD, rapid eye movement (REM) sleep behavior disorder (RBD) [12], [13], ∗[14], ∗[15], restless legs syndrome (RLS) [16] EDS [17], [18], and other sleep-related disorders may already be present. If these disorders are indeed a part of the early pathogenic process of PD, they can potentially help identify individuals at-risk for PD. While the association between RBD and PD is well established ∗[15], ∗[19], it is still under debate whether people with RLS and EDS are at increased risk for clinical PD [10], [17], [20]. Other sleep disorders, including periodic leg movement in sleep (PLMS), obstructive sleep apnea (OSA), insomnia and circadian sleep–wake cycle disruption also occur in PD [21]. However, it is not clear if these disorders represent a part of the intrinsic pathogenic process of PD, or they simply co-occur due to other factors.
During the recent decades, the rapid development of various genetic methods have led to a wealth of genetic information on familial and sporadic PD. Mutations in genes such as GBA, LRRK2, SNCA, PARK2, PINK1, PARK7, VPS35, SMPD1 and others can lead to PD [22], and at least 45 additional risk factors in 41 genetic loci were associated with increased or decreased risk for PD in genome wide association studies (GWAS) ∗[23], ∗[24]. Similarly, genetic studies of sleep-related disorders have identified multiple genes and loci associated with both increased and decreased risk for these disorders. For example, GWASs of RLS cohorts identified genetic loci that are associated with the risk for RLS [25], and several studies examined the genetic overlap between RLS and PD [26], [27], [28], [29]. Only recently, the first genetic studies of RBD were performed [30], [31], [32] in order to examine whether RBD and PD share a similar genetic background.
The purpose of this review, is first to briefly summarize the clinical associations between PD and sleep-related disorders commonly affecting PD patients. This part will map possible clinical overlaps between PD and sleep-related disorders, which may suggest possible shared etiology. Then, we will discuss the available genetic knowledge on PD and the various sleep disorders potentially associated with PD. By comparing the known genetic factors associated with PD and sleep disorders, we will discuss on the potential overlap in genetics, as an indicator for etiology. We will further discuss the implications of these data on our understanding of PD, its clinical course and future aspects.
Section snippets
Determining the temporal correlates of sleep disorders and Parkinson disease
The majority of PD patients will suffer from a sleep-related disorder, whether before or after the onset of PD [21]. Defining the temporal association between these sleep-related disorders and PD is important for determining whether sleep disorders can be clinical markers for PD development and/or progression. Based upon pathoanatomical considerations, essentially all sleep-related disorders could occur during prodromal PD, yet to determine if they are pathophysiologically associated with PD or
REM sleep behavior disorder
Thus far, the only sleep-related disorder that is unequivocally associated with later development of PD and other synucleinopathies is RBD. RBD is characterized by lack of atonia during REM sleep and acting out of dreams ∗[15], [33]. After the initial report on high conversion rates from RBD to synucleinopathies [14], various reports had confirmed that individuals with RBD are likely to progress to an overt synucleinopathy in a time-dependent manner ∗[15], ∗[19], [34], [35], [36], [37]. Fig. 1
Genetics of Parkinson disease – a brief overview
Once considered a purely sporadic, environmental disease, PD is known today to have a strong genetic component. Estimates of the contribution of heredity to the risk for PD range between 27% and 60% in population and familial based studies [74], [75]. So far, over 40 genetic loci and genes have been linked to PD and parkinsonism, including variants that are associated with mildly increased or decreased risk for PD, variants that are strong risk factors for PD, and mutations that necessarily
Genetic overlap between RBD and PD
Although the association between RBD and PD was initially reported 2 decades ago, only recently genetic studies that specifically focus on RBD have been performed. The strongest genetic association reported thus far, is with mutations in GBA [32], [102]. Clinically, GBA-associated PD and RBD-associated PD have many similarities. Both GBA and RBD are associated with rapid motor progression [103], [104] and the postural-instability-gait-dysfunction phenotype [105], [106], autonomic dysfunction
Restless legs syndrome, periodic leg movements during sleep and Parkinson disease genetics
The largest published RLS GWAS included 922 cases and 1526 controls in the discovery phase and 3935 cases and 5754 controls in the replication phase [25]. While this is not as large as the PD GWASs [24], it is large enough to provide reliable results. Thus far, six genes and genetic loci were associated with RLS in GWASs: MEIS1, BTBD9, PTPRD, MAP2K5/SKOR1, TOX3 and the intergenic rs6747972 on chromosome 2 [25]. Given the strong clinical overlap between RLS and PLMS, it is not surprising that
Obstructive sleep apnea genetics and Parkinson disease
Studying the genetics of OSA is complicated by comorbidities that can predispose to OSA and are also heritable. These comorbidities can be divided into four major groups: 1) obesity and metabolic disturbances, 2) craniofacial and upper airway morphology, 3) ventilation control, and 4) sleep and circadian rhythm control. It is also likely that other genes unrelated to these conditions may also be risk factors for OSA. For example, family studies that demonstrated that first-degree relatives of
Circadian sleep–wake cycle disruption genetics and Parkinson disease
Many of the genes and proteins regulating the circadian clock are well characterize, including PER1, PER2, PER3, CRY1, CRY2, CLOCK, ARNTL, ARNTL2, CSNK1D, CSNK1E, TIMELESS, NPAS2, NR1D1, DBP, FBXL3, BHLHE40, BHLHE41 and others that were thoroughly reviewed [148], [149], [150]. It important to note that most of the knowledge on the function of these genes and proteins is derived from animal studies [151], therefore the role of human genetic variations in these genes and their potential effects
Genetics of insomnia and excessive daytime sleepiness
Genetic studies of both insomnia and EDS are complicated by the various factors that are associated with these two conditions. Therefore, identifying genes and variants specifically associated with insomnia and EDS is challenging, which may explain the relatively low number of genetic studies of these conditions [163]. Since EDS can be related to circadian sleep–wake cycle disruption, PLMS and other sleep disorders that were reviewed here, the same genes involved in these disorders can also be
Conclusions
Generally, the genetic study of sleep-related disorders still lags behind other medical fields, although in recent years some progress has been made. Only a few GWASs have been performed in sleep disorders, and while basic genetic twin and familial studies had been performed in the past, there are very few studies that applied next generation sequencing technologies on families with sleep-related disorders. So far, there is no evidence for overlap in genetic predisposition for PD and either
Conflicts of interest
ZGO received consultation and travel fees from Sanofi-Genzyme and Lesosomal Therapeutics Inc. (LTI). RNA received consultation and travel fees from Sanofi-Genzyme and Prophase, GAR reports no conflict of interests, RBP received funding for consultancy from Biotie, Roche, Biogen, and speaker fees from Teva and Novartis.
Acknowledgements
We thank Jay Ross for reading the manuscript and providing useful comments. ZGO is supported by a postdoctoral fellowship from the Canadian Institutes for Health Research (CIHR) and received grants from the Michal J. Fox Foundation for Parkinson's research. GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. RBP received grants from the Fonds de la Recherche en Sante Quebec, CIHR, Parkinson Society Canada, the Weston-Garfield
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