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.

Myotonic dystrophy, excessive daytime sleepiness, MSLT, SOREMP, hypocretin, orexin