Melatonin is effective in treating sleep problems in Angelman syndrome but problems in metabolising melatonin may be part of the Angelman phenotype

Abstract

Background: Sleep problems are frequent in Angelman syndrome and often severe. Previous studies suggested that melatonin improves sleep in insomniac patients with Angelman syndrome. Method: We performed a randomized placebo‐controlled study in eight children with Angelman syndrome with chronic insomnia. Patients received, depending on age, either melatonin 5 or 2.5 mg, or placebo. Parents recorded lights off time, sleep onset, night wakes, wake‐up time and epileptic seizures in a diary. After the 4‐week placebo controlled phase of the study, all patients received 4 weeks open treatment with melatonin. We present data on these eight patients and 20 new AS patients that we treated in our clinic and did not describe in this study. Results: In our randomized study melatonin significantly advanced sleep onset by 28 min., decreased sleep latency by 32 min., increased total sleep time by 56 min., reduced the number of nights with wakes from 3.1 to 1.6 nights a week. After 4 weeks of open treatment however, there was in some patients a tendency to a reduction in therapeutic gain. Salivary endogenous melatonin levels, measured at baseline and at the last evening of the fourth treatment week when no study medication was taken, showed a marked increase. In AS patients in whom the melatonin lost its effect, melatonin levels had become extremely high, whereby the normal 24h melatonin rhythm was lost. Discussion: Four weeks of melatonin treatment in Angelman syndrome children with chronic insomnia was more effective in decreasing sleep latency, advancing sleep onset, reducing number of night wakes and increasing total sleep time than placebo. However, after several weeks melatonin lost its beneficial effect in most AS patients. We found indications that melatonin metabolism in AS is disturbed and that this possibly is part of the AS phenotype.