F179. Notched delta, epilepsy and Angelman’s syndrome genetics

Abstract

Introduction Angelman syndrome (AS) is a neurogenetic disorder resulting from a deletion of the maternal 15q11.2-13.1 region, mutation of maternal UBE3A gene, paternal uniparental disomy of chromosome 15, or methylation imprinting defect. Epilepsy affects the majority of the patients. Notched delta (ND) is characterized by ill-defined mixed spikes among a diffuse delta slowing, giving a “notched” appearance seen in AS. The aim of this study was to evaluate the prevalence of ND and epilepsy among the known genetic mechanisms. Methods Patients with AS seen at the Mayo Clinic Medical Genetics Clinics between September 2006 and September 2017 were identified. Medical records were reviewed for epilepsy history and EEG findings. The first 4 available EEG reports were reviewed for presence of ND. Patients were classified into 4 genetic groups: 1. microdeletion, 2.uniparental disomy (UPD), 3.UBE3A mutation, or 4.methylation defect. Patients without research consent (n = 1), inadequate epilepsy or EEG records (n = 3) were excluded. The age at seizure onset and the prevalence of ND was calculated in each genetic group. Fisher exact tests and nonparametric Wilcoxon rank sum test were used. Results Twenty-four patients were included (male 42%, median age 14.1 years, IQR 8.4–25.8). Genetic etiology was microdeletion 13, UPD 1, UBE3A mutation 4, and methylation defect 6. Epilepsy was present in 21/24 (88%) patients. There was no difference in the prevalence of epilepsy among the different genetic groups (microdeletion 12/13, UPD 1/1, UBE3A mutation 3/4, methylation defect 5/6, p > 0.05). Patients without seizure were younger than those with epilepsy (No seizure median age 7.4 years, IQR 2.6–8.4 vs Epilepsy 17.3 years, IQR 9.6–27.5, p = 0.03). Among epilepsy patients, the median age of seizure onset was 2 years, IQR 0.5–3.7. Patients with microdeletion have earlier age of seizure onset compared to the other groups: microdeletion, n = 12, median age of seizure onset 1.3 years, IQR 0.5–2.0; UPD, n = 1, age of seizure onset 3.0 years; UBE3A mutation, n = 3, median age of seizure onset 4.3 years, IQR 2.7–5.2; methylation defect, n = 5, median age of seizure onset, 3.8 years IQR 1.7–5.1; p = 0.03. ND was recognized in 15/24 (62%) patients at any time, including 8/13 chromosomal microdeletion, 1/1 UPD, 2/4 UBE3A mutation, 4/6 methylation defect. The median age at which ND was first recognized was 9.2 years, IQR 2.83–18.2. Prevalence of epilepsy was no different between patients with or without ND (13/15 patient ND and 8/9 patients without ND, p > 0.05). Conclusion Epilepsy was invariably present in the majority of the different genetic groups of AS patients, with earlier age of onset in the chromosome 15 microdeletion group. Patients with seizures were older than those without which may suggest an age related increased risk for developing epilepsy. ND was recognized in nearly two-thirds of all patients, with no specific distribution among the different genetic etiologies and did not influence the prevalence of epilepsy.