Decreased hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness

Abstract

Study Objectives: Myotonic dystrophy type 1 is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment. This disorder is caused by a CTG triplet expansion in the 3′ untranslated region of the DMPK gene on 19q13. Myotonic dystrophy type 1 is frequently associated with excessive daytime sleepiness, sharing with narcolepsy a short sleep latency and the presence of sleep-onset rapid eye movement periods during the Multiple Sleep Latency Test. Since narcolepsy is characterized by a dysfunction of the hypothalamic hypocretin system, we investigated whether patients with myotonic dystrophy type 1 with excessive daytime sleepiness have abnormalities in the hypocretin system. Design/Participants: Six patients with myotonic dystrophy type 1 complaining of excessive daytime sleepiness and 13 healthy controls without a sleep disorder were included. The patients with myotonic dystrophy type 1 were evaluated using clinical interviews, nocturnal polysomnograms, and Multiple Sleep Latency Tests. All patients had a confirmed genetic diagnosis for DM1 and were HLA typed. Cerebrospinal fluid hypocretin-1 levels were measured using a direct radioimmunoassay in patients and controls. Setting: University hospital sleep laboratory. Interventions: N/A. Measurement and Results: The mean sleep latency on Multiple Sleep Latency Tests was abnormal in all patients (<5 minutes in 2, ≤8 in 4) and 2 sleep-onset rapid eye movement periods were observed in 2 subjects. All patients were HLA-DQB1*0602 negative. Hypocretin-1 levels were significantly lower in patients versus controls (p<0.001); 1 case with 2 sleep-onset rapid eye movement periods had hypocretin-1 levels in the range generally observed in narcolepsy (<110 pg/mL). Three cases had intermediate levels (110-200 pg/mL). Hypocretin-1 levels did not correlate clinically with disease severity or duration or with subjective or objective sleepiness reports. Conclusions: A dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal Multiple Sleep Latency Test results in patients with myotonic dystrophy type 1.