Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors

Abstract

Objective: Excessive daytime sleepiness is a common symptom in Prader Willi syndrome (PWs). Sleep disordered breathing (SDB) and narcoleptic traits such as REM sleep onsets (SOREMPs) have been reported in these subjects. We evaluated nighttime and daytime sleep patterns in patients with PWs in order to clarify the nature of their hypersomnia.

Design and methods: We performed overnight continuous EEG-polysomnographic studies (with breathing monitoring included) in 14 subjects (6 M,8 F; mean age 17 years, range 8–37) affected by PWs unselected for sleep disturbances. Ten patients underwent a Multiple Sleep Latency Test (MSLT) the day following the nocturnal sleep studies. Patients assessment was completed by means of immunogenetic characterization.

Results: Nocturnal polysomnographic investigation documented sleep related breathing abnormalities such as central apneas, hypopneas or hypoventilation which mainly occurred during REM sleep in 8 subjects and did not cause sleep disruption. Only 4 subjects presented an increase in the Respiratory Disorder Index (RDI) slightly above the normal limits. In 8 subjects out of 10, with and without SDB, the mean daytime sleep latency could be considered abnormal according to the Tanner staging of pubertal development. Five patients showed at least two SOREMPs at MSLT. Subjects with and without SOREMPs had, respectively, a mean age of 18.6 SD 7.9 (4 M, 1 F) and 14.5 SD 2.9 (4 F, 1 M). The paternal deletion:uniparental dysomy ratio at genotypic characterization was 4:1 and 3.5:1 in subjects with and without SOREMPs, respectively. No patient presented DR-15 nor Dq-6.

Conclusions: Excessive sleepiness is a frequent disturbance in PWs. Subgroups of PW patients show hypersomnolence and SOREMPs. Sleep disordered breathing appears to have a limited role in the genesis of hypersomnia which not seems on the other hand attributable to the coexistence of narcolepsy phenotype. Hypersomnia in PW syndrome is likely to mainly be attributable to a primary hypothalamic dysfunction. The potential interacting role of other factors such as subjects age, sex and genetic pattern is suggested and deserve further investigation.

Introduction

Excessive daytime sleepiness is a frequent disturbance in Prader Willi syndrome (PWs). Nonetheless relatively few clinical and/or instrumental sleep studies regarding this pathology have been reported (Donaldson et al., 1994). Hypersomnolence in PWs is clinically polymorphic and its origin has not been fully clarified. The various clinical and electrophysiological expressions of this symptom in PWs include: continuous hypersomnolence with and without REM sleep onset periods (SOREMPs) at nocturnal PSG and/or at Multiple Sleep Latency Test (MSLT) and periodic hypersomnolence like that seen in Kleine–Levin syndrome (Clarke et al., 1989, Vela-Bueno et al., 1984, Gau et al., 1996).

Because of obesity, cranio-facial dysmorphism and muscular hypotonia, PWs patients are considered at risk for sleep disordered breathing (SDB) which, in turn, could explain hypersomnolence. However hypersomnolent PWs patients without SDB or with SDB too mild to fully explain hypersomnolence (Vela-Bueno et al., 1984, Hertz et al., 1993), have been reported. Furthermore persistence of excessive daytime sleepiness in PWs patients after weight loss and reduction of pre-existing SDB and after Continuous Positive Air Pressure (CPAP) treatment has been documented (Sforza et al., 1991, Harris and Allen, 1996).

The pattern of hypersomnolence with SOREMPs at MSLT and/or at nocturnal polysomnography suggested a possible relationship between PWs and narcolepsy. In fact, although SOREMPs are observed in different pathological and physiological conditions, they are considered to be the main diagnostic feature of narcolepsy (Reynolds et al., 1982, Mitler et al., 1979, Aldrich et al., 1997).

It has been hypothesized that the pattern of hypersomnia in PWs may be an expression of the hypothalamic dysfunction which characterizes PWs per se, rather than a symptom of narcolepsy (Vgontzas et al., 1996a, Parkes, 1999).

In this study a clinical and electrophysiological assessment of nocturnal sleep and daytime vigilance was carried out on14 PWs patients, unselected for sleep disturbances. Patient assessment was completed by means of immunogenetic characterization.