Polisomnographic phenotype is linked with genetic findings in Prader–Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is a rare genetic disorder, usually sporadic, affecting 1/25,000 births, in which a critical region of chromosome 15 (15q11-q13) is affected. At birth, PWS infants exhibit characteristic facial features, small hands and feet, severe hypotonia with suckling and swallowing troubles, delay in psychomotor development and lethargy. After this initial phase, hyperphagia and absence of satiety (severe obesity and sleep apneas), growth hormone deficiency (short stature) and incomplete pubertal development are striking signs. Diagnosis is based on clinical criteria confirmed by genetic study, showing a deletion (DEL) or, less frequent and less severe, uniparental disomy (UPD). Eight newborn with dysmorphic features, weak reactivity to stimuli and hypotonia were evaluated. Genetic findings confirmed or excluded PWS diagnosis. Patients underwent a daily polysomnographic study (EEG, EOG, EMG, ECG, nasal airflow, respiratory movements and oxymetry); sleep and associated events were scored based on international rules for newborns (Anders et al., 1971). In 5 cases, CSF Hcrt-1 was measured. Genetic study confirmed PWS in 6 cases (DEL, n = 5 ; UPD, n = 1). Mean value of CSF Hcrt-1 in PWS-patients was 106.7 ± 16.9 pg/ml (>220 in non-PWS infants). EEG tracing was normal in 7 infants according to postconceptional age (one with slightly generalized slowing). The most relevant finding was a dramatic reduction of arousals and reactivity to stimuli, more severe in DEL-PWS, moderate in UPD-PWS and absent in non-PWS hypotonic infants (mean arousal index 4.1 /h, 5.4 /h and 14 /h; mean fragmentation index 4.1 /h, 18.3 /h and 21 /h). No significant respiratory events were recorded and other sleep parameters were similar to those seen in healthy neonates evaluated in our hospital. Sleep disturbances are already found in newborns, even before respiratory events appear. This data suggests that lack of reactivity to stimuli in newborns may be related to difficulty in regulation of sensory stimuli, leading to further symptoms of PWS (poor satiety recognition, decreased sensitivity to pain and sleep disorders). This generalized hypoarousal-state could be the primary mechanism underlying the sleep abnormalities in PWS patients. We thank Dr. J. Santamaría (H. Clinic, Barcelona, Spain) for his cooperation in typing and measurement of cerebrospinal fluid hypocretin-1 level.