Decreased Hypocretin-1 (Orexin-A) Levels in the Cerebrospinal Fluid of Patients with Myotonic Dystrophy and Excessive Daytime Sleepiness

Abstract

A dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal Multiple Sleep Latency Test results in patients with myotonic dystrophy type 1.

The hypocretin neurotransmission system in myotonic dystrophy type 1

“…Results of the present study differ from a previous study of six patients with DM1, in which one patient had Hcrt-1 levels below110 pg/mL in CSF, and three patients had Hcrt-1 levels between 110 and 200 pg/mL, 25 a range that is intermediate between levels observed in normal individuals and patients with narcolepsy. 23 By contrast, only 3 of 38 patients with DM1 in the current study, as compared to 2 of 33 controls, had levels in this intermediate range.…”

“…23 Hereditary narcolepsy in dogs is caused by mutations that affect splicing in the hypocretin receptor 2 (HcrtR2) gene. 24 Recently it was reported that Hcrt-1 was reduced in CSF in patients with DM1 25 and that sleep onset REM, similar to that observed in narcolepsy, was observed in patients with DM1. 15,16 To determine if DM1 is associated with abnormal Hcrt-1 action, we carried out a prospective study of CSF Hcrt-1 in patients with DM1 who did or did not have EDS.…”

“…served 15,16 ; 2) polysomnographic abnormalities in DM1 do not consistently correlate with evidence of sleep-disordered breathing 17 ; 3) adequate treatment of sleep-disordered breathing does not always improve EDS 18,19 ; 4) pulsatile secretion of cortisol and growth hormone is disrupted in DM1, suggesting a general disturbance of hypothalamic regulation and circadian rhythm 20,21 ; and 5) central hypoventilation and hypersomnia were correlated in some patients with DM1 with autopsy findings of neuronal loss in the reticular formation and dorsal raphe. 22 Based on previous observations of reduced Hcrt-1 25 and SOREMP in patients with DM1, 15,16 we postulated that EDS in DM1 may result from decreased Hcrt-1 release or misregulated Hcrt receptor splicing. Against our hypothesis, we found that none of 38 patients with DM1 in our cohort showed Hcrt-1 reductions in a range that is typically associated with narcolepsy (below 110 pg/mL in CSF).…”

Cerebral involvement in myotonic dystrophies

“…One report documented abnormal protein content in a subset of patients with DM1, 43 the significance of which is unclear. More recently, Martinez-Rodriguez et al 68 reported decreased orexin-A levels in the cerebrospinal fluid of 3 of 9 patients with DM1 affected by excessive daytime sleepiness, thus suggesting analogies with the mechanisms involved in narcolepsy.…”

Neuromuscular disorders and sleep

“…There is evidence to suggest complex, widespread malfunction of circadian and ultradian timing system, including neuroendocrine abnormalities in sleep. The patients complaining of excessive daytime sleepiness, with 39% to 77% of patients reporting, often require, in addition to measures to correct SDB, stimulant medication [37].…”