Emily Hanzlik1, Sarah A Klinger1, Robert Carson1, Jessica Duis2. 1. Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. 2. Medical Genetics & Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract
STUDY OBJECTIVES: Angelman syndrome (AS) is a rare neurodevelopmental disorder that is characterized by developmental delay, intellectual disability, seizures, a characteristic happy personality, gait ataxia, tremulousness of the limbs, microcephaly, and anxiety. Severe sleep disturbances with the diminished need for sleep and abnormal sleep-wake cycles are seen in up to 90% of patients with AS. AS is caused by absent maternal expression of the gene UBE3A located in the 15q11.2-q13 locus. We hypothesized that selective antagonism of 5-HT₂ and 5-HT₃ serotonin receptors with mirtazapine would benefit sleep disturbances in patients with AS. METHODS: Institutional Review Board approval was obtained at Vanderbilt University Medical Center. Medical records of individuals seen in the Comprehensive Angelman Syndrome clinic were retrospectively reviewed to determine the use of mirtazapine for disordered sleep. Parents were asked to respond to a survey to assess the phenotypic features of sleep and behavioral disturbances in AS. They were asked about the use of medications for sleep, focusing on the benefits and risks of mirtazapine. RESULTS: A cohort of 8 individuals with AS, ranging in age from 3 to 16 years old with histories of sleep challenges, were treated with 3.75 to 30 mg of mirtazapine at bedtime for 0 to 36 weeks. Nocturnal awakenings were the most common sleep challenge reported. Seven of eight patients reported benefits from mirtazapine, including increased total sleep time, decreased nocturnal awakenings, and decreased time to fall asleep. The most significant side effects of mirtazapine were hyperphagia and weight gain. CONCLUSIONS: Individuals with AS have abnormal sleep-wake cycles and a high unmet medical need. Mirtazapine helped with sleep onset and nighttime awakenings in 7 of 8 patients, with 2 patients reporting a positive benefit with respect to behavior. These data suggest that mirtazapine may be considered for the treatment of sleep difficulties in patients with AS who remain refractory to more conventional therapies. Weight gain was a common side-effect and led to discontinuation of treatment in 1 patient.
STUDY OBJECTIVES:Angelman syndrome (AS) is a rare neurodevelopmental disorder that is characterized by developmental delay, intellectual disability, seizures, a characteristic happy personality, gait ataxia, tremulousness of the limbs, microcephaly, and anxiety. Severe sleep disturbances with the diminished need for sleep and abnormal sleep-wake cycles are seen in up to 90% of patients with AS. AS is caused by absent maternal expression of the gene UBE3A located in the 15q11.2-q13 locus. We hypothesized that selective antagonism of 5-HT₂ and 5-HT₃ serotonin receptors with mirtazapine would benefit sleep disturbances in patients with AS. METHODS: Institutional Review Board approval was obtained at Vanderbilt University Medical Center. Medical records of individuals seen in the Comprehensive Angelman Syndrome clinic were retrospectively reviewed to determine the use of mirtazapine for disordered sleep. Parents were asked to respond to a survey to assess the phenotypic features of sleep and behavioral disturbances in AS. They were asked about the use of medications for sleep, focusing on the benefits and risks of mirtazapine. RESULTS: A cohort of 8 individuals with AS, ranging in age from 3 to 16 years old with histories of sleep challenges, were treated with 3.75 to 30 mg of mirtazapine at bedtime for 0 to 36 weeks. Nocturnal awakenings were the most common sleep challenge reported. Seven of eight patients reported benefits from mirtazapine, including increased total sleep time, decreased nocturnal awakenings, and decreased time to fall asleep. The most significant side effects of mirtazapine were hyperphagia and weight gain. CONCLUSIONS: Individuals with AS have abnormal sleep-wake cycles and a high unmet medical need. Mirtazapine helped with sleep onset and nighttime awakenings in 7 of 8 patients, with 2 patients reporting a positive benefit with respect to behavior. These data suggest that mirtazapine may be considered for the treatment of sleep difficulties in patients with AS who remain refractory to more conventional therapies. Weight gain was a common side-effect and led to discontinuation of treatment in 1 patient.
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Authors: Jessica Duis; Mark Nespeca; Jane Summers; Lynne Bird; Karen G C B Bindels-de Heus; M J Valstar; Marie-Claire Y de Wit; C Navis; Maartje Ten Hooven-Radstaake; Bianca M van Iperen-Kolk; Susan Ernst; Melina Dendrinos; Terry Katz; Gloria Diaz-Medina; Akshat Katyayan; Srishti Nangia; Ronald Thibert; Daniel Glaze; Christopher Keary; Karine Pelc; Nicole Simon; Anjali Sadhwani; Helen Heussler; Anne Wheeler; Caroline Woeber; Margaret DeRamus; Amy Thomas; Emily Kertcher; Lauren DeValk; Kristen Kalemeris; Kara Arps; Carol Baym; Nicole Harris; John P Gorham; Brenda L Bohnsack; Reid C Chambers; Sarah Harris; Henry G Chambers; Katherine Okoniewski; Elizabeth R Jalazo; Allyson Berent; Carlos A Bacino; Charles Williams; Anne Anderson Journal: Mol Genet Genomic Med Date: 2022-02-11 Impact factor: 2.183