Low vitamin D in narcolepsy with cataplexy

Background

Narcolepsy with cataplexy (NC) is currently thought to be an autoimmune-mediated disorder in which environmental risk factors make a significant contribution to its development. It was proposed that vitamin D deficiency plays a role in autoimmune diseases. Here we investigated whether NC can be associated with 25-hydroxyvitamin D (25(OH)D) level deficiency in patients with NC compared with gender- and age-matched normal controls.

Methodology

Serum level of 25 (OH)D was determined in 51 European patients with typical NC compared to 55 age-, gender-, and ethnicity-matched healthy controls. Demographic and clinical data (age at onset, duration and severity of disease at baseline, and treatment intake at time of study) and season of blood sampling were collected to control for confounding variables.

Principal Findings

Serum 25(OH)D concentration was lower in NC compared to controls (median, 59.45 nmol/l [extreme values 24.05–124.03] vs. 74.73 nmol/l [26.88–167.48] p = 0.0039). Patients with NC had significantly greater vitamin D deficiency (<75 nmol/l) than controls (72.5% vs 50.9%, p = 0.0238). Division into quartiles of the whole sample revealed that the risk of being affected with NC increased with lower 25(OH)D level, with a 5.34 OR [1.65–17.27] for the lowest quartile (p = 0.0051). Further adjustment for BMI did not modify the strength of the association (OR: 3.63, 95% CI = 1.06–12.46, p = 0.0191). No between BMI and 25(OH)D interaction, and no correlation between 25(OH)D level and disease duration or severity or treatment intake were found in NC.

Conclusion

We found a higher frequency of vitamin D deficiency in NC. Further studies are needed to assess the contribution of hypovitaminosis D to the risk of developing narcolepsy, and to focus on the utility of assessing vitamin D status to correct potential deficiency.     

Decision making and addictive behaviors in narcolepsy with cataplexy

Narcolepsy with cataplexy (NC) is caused by the loss of hypothalamic neurons that produce hypocretins (also known as orexins). The hypocretin system plays a crucial role in sleep, wakefulness, and energy homeostasis. Behavioral, anatomical and neurophysiological studies in animals have shown that hypocretins are involved in reward and addictive behaviors. Recently neuroimaging and behavioral studies indicated that reward-processing and decision-making networks are also altered in hypocretin-deficient narcoleptic patients. These evidences offer new research directions to our understanding of the role of hypocretins in reward and addiction.

     

A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score = 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders.     

Sleep disorders: Is hypocretin involved in sleep,wakefulness, narcolepsy,and/or cataplexy?

Sleep and Biological Rhythms -     

Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy

REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.     

Anomalous hypothalamic responses to humor in cataplexy

Background

Cataplexy is observed in a subset of patients with narcolepsy and affects approximately 1 in 2,000 persons. Cataplexy is most often triggered by strong emotions such as laughter, which can result in transient, yet debilitating, muscle atonia. The objective of this study was to examine the neural systems underlying humor processing in individuals with cataplexy.

Methodology/Principal Findings

While undergoing functional Magnetic Resonance Imaging (fMRI), we showed ten narcolepsy-cataplexy patients and ten healthy controls humorous cartoons. In addition, we examined the brain activity of one subject while in a full-blown cataplectic attack. Behavioral results showed that participants with cataplexy rated significantly fewer humorous cartoons as funny compared to controls. Concurrent fMRI showed that patients, when compared to controls and in the absence of overt cataplexy symptoms, showed pronounced activity in the emotional network including the ventral striatum and hypothalamus while viewing humorous versus non-humorous cartoons. Increased activity was also observed in the right inferior frontal gyri -a core component of the inhibitory circuitry. In comparison, the one subject who experienced a cataplectic attack showed dramatic reductions in hypothalamic activity.

Conclusions

These findings suggest an overdrive of the emotional circuitry and possible compensatory suppression by cortical inhibitory regions in cataplexy. Moreover, during cataplectic attacks, the hypothalamus is characterized by a marked decrease in activity similar to that observed during sleep. One possible explanation for these findings is an initial overdrive and compensatory shutdown of the hypothalamus resulting in full cataplectic symptoms.     

Nocturnal polysomnographic characteristics of pediatric narcolepsy

The aim of this study was to describe the polysomnographic features of childhood-onset narcolepsy. A retrospective review was performed on children with narcolepsy. The polysomnogram findings were compared with reference values obtained from normative data in the general population. Narcolepsy subjects had a mean initial sleep latency of 10.9 min on nocturnal PSG, which was shorter by a mean of 18 min than corresponding values from normative data (P < 0.001). Short initial REM latency on nocturnal PSG correlated with the number of SOREMPs on MSLT in subjects with narcolepsy (P = 0.007). These findings may assist in the clinical diagnosis of narcolepsy.

     

A female with Coffin-Lowry syndrome and "cataplexy"

Coffin-Lowry syndrome (CLS) is an X-linked semidominant condition, caused by mutations in the gene encoding the ribosomal protein S6 kinase-2 (RSK-2), a growth factor regulating protein kinase, which is mapped to Xp 22.2. The syndrome is mainly seen in males. It is manifested by moderate to severe mental retardation and characteristic facial, hand and skeletal malformations. We present a female patient with fully manifested CLS, confirmed by molecular analysis, who experienced daily drop episodes, diagnosed as "cataplexy". The episodes were precipitated by emotional or auditory stimuli and were significantly reduced, by selective serotonine re-uptake inhibitors.     

Immortal orexin cell transplants restore motor-arousal synchrony during cataplexy

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Executive control of attention in narcolepsy

Background

Narcolepsy with cataplexy (NC) is a disabling sleep disorder characterized by early loss of hypocretin neurons that project to areas involved in the attention network. We characterized the executive control of attention in drug-free patients with NC to determine whether the executive deficits observed in patients with NC are specific to the disease itself or whether they reflect performance changes due to the severity of excessive daytime sleepiness.

Methodology

Twenty-two patients with NC compared to 22 patients with narcolepsy without cataplexy (NwC) matched for age, gender, intellectual level, objective daytime sleepiness and number of sleep onset REM periods (SOREMPs) were studied. Thirty-two matched healthy controls were included. All participants underwent a standardized interview, completed questionnaires, and neuropsychological tests. All patients underwent a polysomnography followed by multiple sleep latency tests (MSLT), with neuropsychological evaluation performed the same day between MSLT sessions.

Principal Findings

Irrespective of diagnosis, patients reported higher self-reported attentional complaints associated with the intensity of depressive symptoms. Patients with NC performed slower and more variably on simple reaction time tasks than patients with NwC, who did not differ from controls. Patients with NC and NwC generally performed slower, reacted more variably, and made more errors than controls on executive functioning tests. Individual profile analyses showed a clear heterogeneity of the severity of executive deficit. This severity was related to objective sleepiness, higher number of SOREMPs on the MSLT, and lower intelligence quotient. The nature and severity of the executive deficits were unrelated to NC and NwC diagnosis.

Conclusions

We demonstrated that drug-free patients with NC and NwC complained of attention deficit, with altered executive control of attention being explained by the severity of objective sleepiness and global intellectual level. Further studies are needed to explore whether medications that promote wakefulness can improve the executive functions in narcolepsy.     

Hypocretin/orexin, sleep and narcolepsy

The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy and unusually rapid transitions to rapid-eye-movement sleep, opens a new field of investigation in the area of sleep control physiology. Hypocretin-1 and -2 (also called orexin-A and -B) are newly discovered neuropeptides processed from a common precursor, preprohypocretin. Hypocretin-containing cells are located exclusively in the lateral hypothalamus, with widespread projections to the entire neuroaxis. Two known receptors, Hcrtr1 and Hcrtr2, have been reported. The functional significance of the hypocretin system is rapidly emerging in both animals and humans. Hypocretin abnormalities cause narcolepsy in dogs, human and mice. The role of the hypocretin system in normal sleep regulation is more uncertain. We believe hypocretin cells drive cholinergic and monoaminergic activity across the sleep cycle. Input from the suprachiasmatic nucleus to hypocretin-containing neurons may explain the occurrence of clock-dependent alertness. Other functions are suggested by pharmacological and neurochemical experiments. These include regulation of food intake, neuroendocrine function, autonomic nervous system activity and energy balance.