Decline of CSF orexin (hypocretin) levels in Prader–Willi syndrome

Omokawa, Mayu; Ayabe, Tadayuki; Nagai, Toshiro; Imanishi, Aya; Omokawa, Ayumi; Nishino, Seiji; Sagawa, Yohei; Shimizu, Tetsuo; Kanbayashi, Takashi

doi:10.1002/ajmg.a.37542

Cited by 35 publications

(24 citation statements)

References 30 publications

(39 reference statements)

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“…Among symptomatic narcolepsy, Prader-Willi syndrome, myotonic dystrophy type1 and NPC were known as congenital and developmental disorders [25]. We reported that orexin levels with Prader-Willi syndrome and myotonic dystrophy type1 were higher than idiopathic narcolepsy and lower than idiopathic hypersomnia [28,29]. The orexin levels of NPC were also same as above two diseases (Fig.…”

Section: Discussionmentioning

confidence: 66%

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat

Imanishi

Kawazoe

Hamada

et al. 2020

Orphanet J Rare Dis

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Study objectives Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings. Methods Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients. Results Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels. Discussion Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients’ NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients. Conclusion The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.

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Section: Discussionmentioning

confidence: 66%

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat

Imanishi

Kawazoe

Hamada

et al. 2020

Orphanet J Rare Dis

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“…Dysregulation of the OX system has been reported in a few clinical studies, although to date, the results remain contradictory. One study described an increase in the OX-A level in PWS subjects [47], while another showed a decrease in the peptide in the cerebrospinal fluid [11]. Taken together, these findings call for an alteration of the OX system in PWS, although the contrasting results may also suggest that the loss of function of paternal alleles within the PWS region results in an increased phenotypic variance.…”

Section: Discussionmentioning

confidence: 96%

“…REM sleep intrusions have been reported in several clinical studies in which PWS subjects manifest narcolepsy and express symptoms such as sleep attacks during active wakefulness, cataplexy (a transient loss of muscle tone during wakefulness), sleep paralysis and sleep fragmentation [8]. Narcolepsy is a sleep condition that causes the loss of hypothalamic OX neurons (also known as hypocretin; HCRT) [9], and previous studies have observed that subjects with PWS show OX alterations [10][11][12].…”

mentioning

confidence: 99%

Paternally expressed imprintedSnord116andPeg3regulate hypothalamic orexin neurons

Marta

Matteo

et al. 2019

Preprint

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words: 186; words count: 9525; figures: 4; Supplementary material: figures 6; table 8Conflict of Interest: each author discloses the absence of any conflicts of interest relative to the research covered in the submitted manuscript. Highlights• Snord116 regulates neuronal activity in the lateral hypothalamus (LH), which is time-locked with cortical states of sleep.• Loss of Snord116 reduces orexin neurons in the LH and affects sleep homeostasis and thermoregulation in mice.• Snord116 and Peg3 independently control orexin expression in the LH.• Paternally expressed alleles maximize the patrilineal effects in the control of REM sleep by the LH in mammals. AbstractImprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterised by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely, the orexin (OX) and melanin concentrating hormone (MCH) systems. We observe that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScr m+/p-) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutants. Therefore, we propose that an imbalance between OX-and MCH-expressing neurons in the LH of mutants reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.

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“…In some individuals, hypersomnia may be due to hypothalamic dysfunction. In others, it is associated with a narcolepsy-like phenotype that includes sleep-onset REM periods and sometimes cataplexy [85,86]. Orexin-A (hypocretin-1), a neuropolypeptide important in maintaining wakefulness, is absent or found at very low levels in individuals with narcolepsy type 1 with cataplexy [87,88].…”

Section: Excessive Daytime Sleepiness and Rem Sleep Disturbancesmentioning

confidence: 99%

“…Orexin-A (hypocretin-1), a neuropolypeptide important in maintaining wakefulness, is absent or found at very low levels in individuals with narcolepsy type 1 with cataplexy [87,88]. Intermediate levels of orexin-A are also seen in cerebral spinal fluid of some PWS patients with excessive daytime sleepiness [86,89]. Some success has been reported using the stimulant modafinil for PWS patients with hypersomnia [90,91]; however, it is important to ensure that hypersomnia in these patients is not secondary to severe OSA prior to starting a stimulant.…”

Section: Excessive Daytime Sleepiness and Rem Sleep Disturbancesmentioning

confidence: 99%

Disorders of Sleep and Ventilatory Control in Prader-Willi Syndrome

Gillett

Perez

2016

Diseases

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Prader-Willi syndrome (PWS) is an imprinted genetic disorder conferred by loss of paternal gene expression from chromosome 15q11.2-q13. Individuals with PWS have impairments in ventilatory control and are predisposed toward sleep disordered breathing due to a combination of characteristic craniofacial features, obesity, hypotonia, and hypothalamic dysfunction. Children with PWS progress from failure to thrive during infancy to hyperphagia and morbid obesity during later childhood and onward. Similarly, the phenotype of sleep disordered breathing in PWS patients also evolves over time from predominantly central sleep apnea in infants to obstructive sleep apnea (OSA) in older children. Behavioral difficulties are common and may make establishing effective therapy with continuous positive airway pressure (CPAP) more challenging when OSA persists after adenotonsillectomy. Excessive daytime sleepiness (EDS) is also common in patients with PWS and may continue after OSA is effectively treated. We describe here the characteristic ventilatory control deficits, sleep disordered breathing, and excessive daytime sleepiness seen in individuals with PWS. We review respiratory issues that may contribute to sudden death events in PWS patients during sleep and wakefulness. We also discuss therapeutic options for treating sleep disordered breathing including adenotonsillectomy, weight loss, and CPAP. Lastly, we discuss the benefits and safety considerations related to growth hormone therapy.

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Decline of CSF orexin (hypocretin) levels in Prader–Willi syndrome

Cited by 35 publications

References 30 publications

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat

Paternally expressed imprintedSnord116andPeg3regulate hypothalamic orexin neurons

Disorders of Sleep and Ventilatory Control in Prader-Willi Syndrome

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