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The hypocretin neurotransmission system in myotonic dystrophy type 1

From the Departments of Neurology (E.C., J.E.H., X.L., L.C.L., C.A.T.) and Psychiatry (W.R.P., M.L.P.), University of Rochester, NY; Stanford University (E.M., L.L.), Palo Alto, CA; and Department of Neurology (V.S.), University of Milan, IRCCS Policlinico San Donato, Italy.

Address correspondence and reprint requests to Dr. Emma Ciafaloni, University of Rochester, Department of Neurology, 601 Elmwood Avenue, Box 673, Rochester, NY 14642 Emma_Ciafaloni{at}urmc.rochester.edu

Background: Patients with myotonic dystrophy type 1 (DM1) frequently have symptoms of excessive daytime sleepiness (EDS). Some patients with DM1 show sleep-onset REM, similar to that observed in narcolepsy. Narcolepsy is characterized by impaired hypocretin (Hcrt) neurotransmission.

Objective: To test for dysregulation of Hcrt neurotransmission in a prospective cohort of patients with DM1.

Methods: Hcrt levels in CSF were measured by radioimmunoassay. Sleep physiology was assessed by overnight polysomnography (PSG) and a multiple sleep latency test (MSLT). Splicing of Hcrt receptor 1 and 2 (HcrtR1 and HcrtR2) mRNA was examined in postmortem samples of temporal cortex.

Results: Seventeen of 38 patients with DM1 reported symptoms of EDS. Among patients with DM1 with EDS who underwent PSG/MSLT, 7 of 13 showed reduced sleep latency, sleep-onset REM, or both. However, CSF Hcrt levels in DM1 (mean 277 pg/mL, n = 38) were not different from controls (mean 277 pg/mL, n = 33). Also, splicing of HcrtR1 and HcrtR2 mRNA in patients with DM1 was similar to controls.

Conclusions: Excessive daytime sleepiness and dysregulation of REM sleep occur frequently in patients with myotonic dystrophy type 1 (DM1). However, the pathophysiologic basis is distinct from narcolepsy, as patients with DM1 do not have a consistent defect of Hcrt release or receptor splicing.

Abbreviations: AHI = apnea/hypopnea index; DM1 = myotonic dystrophy type 1; EDS = excessive daytime sleepiness; ESS = Epworth Sleepiness Scale; Hcrt = hypocretin; MIRS = Muscular Impairment Rating Scale; MSL = mean sleep latency; MSLT = multiple sleep latency test; PLM = periodic limb movement; PSG = polysomnography; SL = sleep onset latency; SOREMP = sleep onset REM periods; UM = University of Milan, Italy; URMC = University of Rochester Medical Center.

Supplemental data at www.neurology.org

This work comes from the University of Rochester Senator Paul Wellstone Muscular Dystrophy Cooperative Research Center (grant U54NS48843-03), with support from the Muscular Dystrophy Association, NIH (AR049077), and University of Rochester General Clinical Research Center (RR00044). This study utilized The National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy (FSHD) patients and family members at the University of Rochester (NIH-Contract N01-AR-5-2274).

Disclosure: The authors report no conflicts of interest.

Received February 16, 2007. Accepted in final form July 2, 2007.