Distinctive EEG abnormalities and seizures occur in Angelman syndrome (AS). 1 Most patients with AS have deletion of maternal chromosome 15q11-13, which comprises three genes of the ␥-aminobutyrate-A (GABA A ) receptor subunit; i.e., GABRB3, GABRA5, and GABRG3 (GABARs). 2 The more severe phenotype in the deletion group often includes intractable epileptic attacks, such as atypical absence and myoclonic seizures. 3 Here, we describe two patients with AS who had refractory atypical absence and were successfully treated with high serum level of ethosuximide (ESM) in addition to valproate (VPA). We also discuss the role of GABARs in the pathogenesis of epilepsy in AS.Case reports. Patient 1. A female infant was born to nonconsanguineous parents. From 5 months of age, she had epilepsy and developmental deterioration. At 8 months of age, she was diagnosed with AS on the basis of deletion of 15q13.1 by fluorescence in situ hybridization (FISH). An initial EEG showed synchronous high-voltage delta wave with bilateral occipital spikes. Her seizures and EEG were well controlled with VPA and clonazepam (CZP). At the age of 1 year 9 months, she began to have frequent atypical absence seizures. Since 2 years 0 months of age, atypical absence status occurred repeatedly, in association with further neurologic deterioration. Then, the peak serum concentration of VPA was 93.6 g/mL and CZP was 54.8 ng/mL. Her waking EEG showed diffuse delta activity and 1.5 Hz paroxysmal high-voltage spike and wave complex bursts (figure, a). The paroxysms corresponded to her clinical absence seizures. Following no beneficial effect of clobazam, ESM was added to VPA. After the addition of ESM, her absence seizures were apparently reduced. When her absence seizures completely disappeared, the concentration of ESM reached 133.6 g/mL; that of VPA decreased to 54.9 g/mL. On EEG, 1.5 Hz high-voltage spike and wave complex bursts also disappeared (see figure, b and c). Thereafter, she gradually showed neurologic recovery.Patient 2. A girl was first referred to our clinic at 8 months of age for delayed development and refractory epileptic seizures, such as astatic seizure and tonic seizure. At 9 months of age, FISH analysis revealed 15q11.2-13 deletion, confirming the diagnosis of AS. Her EEG showed irregular high-voltage delta waves with multifocal sharp waves. VPA was effective for her tonic seizure and melatonin appeared to be effective for her astatic attacks. At the age of 1 year 4 months, she began to have frequent brief atypical absence seizures. Increasing VPA from a concentration of 46.1 g/mL to 93.8 g/mL, her absence seizures disappeared, but high-voltage delta waves on EEG persisted. Two months later, her absence seizure recurred. Then, the ESM was