High-dose ethosuximide for epilepsy in Angelman syndrome: Implication of GABA _A receptor subunit

Abstract

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

Pharmacologic Evidence for Abnormal Thalamocortical Functioning in GABAA Receptor β3 Subunit–Deficient Mice, a Model of Angelman Syndrome

“…We postulate that abnormal thalamocortical synchrony in GABRB3‐deficient AS children and mice, caused by impaired reticular thalamic reciprocal inhibition, causes major interference with normal processing of neural inputs, in effect creating an encephalopathy, and disrupts normal cerebral functional maturation. Our observation in mice and those of Sugiura et al (49) in AS of EEG normalization by ESM raises an intriguing possibility. The question is whether the rectification of thalamocortical physiology, starting at an early age, would improve the cognitive and motor outcome of GABRB3‐deficient mice or humans.…”

“…Our finding that VPA and CZP are quite effective against epileptiform activity in gabrb3‐deficient mice is consistent with a survey of AS caregivers that revealed that these drugs are among those popularly used to treat AS (48). Our observation that ESM exerts marked effects on both slow‐wave activity and interictal spiking in gabrb3‐deficient mice is paralleled by a clinical report that this drug effectively suppresses EEG abnormal delta wave and epileptiform activity and controls atypical absence seizures (49).…”

Epilepsy in patients with Angelman syndrome

“…On the contrary, epilepsy was worsened by carbamazepine (CBZ), oxacarbazepine and vigabatrin[31]. Topiramate (Franz et al[32]) and ethosuximide (Sugiura et al[33]) were successful in small samples of AS patients with drug resistant epilepsy.…”

Angelman Syndrome

“…[61] In adult patients with AS, impairment can resemble girls with Rett syndrome, [58] but children phenobarbital (phenobarbitone) is also effective. [61] In adult patients with AS, impairment can resemble girls with Rett syndrome, [58] but children phenobarbital (phenobarbitone) is also effective.…”