Angelman syndrome in three siblings: genetic model of epilepsy associated with chromosomal DNA deletion of the GABAA receptor.

Abstract

Angelman described 3 patients with sporadic brachycephaly associated with microcephaly, profound mental retardation, easily provoked laughter, and seizures.' We observed 3 siblings with Angelman syndrome (AS) and molecular deletions of chromosome 15.5 Recently in these siblings, we also reported deletion of the y aminobutylic acid (GABA), receptor /?,-subunit which Wagstaff et first reported in AS patients'. GABA is the major inhibitory neurotransmitter in the mammalian brain, and our family is of great interest when considering the relation between recurrent seizures and DNA deletion in chromosomes. Here we describe the neurological and genetic findings of these 3 siblings, and discuss whether AS can be considered as a model of epilepsy associated with chromosomal DNA deletion of the GABA, receptor. ported." Subsequent data and a brief summary are shown in Table 1. The first seizure episode in the 3 patients developed at the ages of 16, 16, and 19 months, respectively. The seizure type in all of the 3 siblings was generalized seizure with no partial seizures seen. The interictal EEGs in the 3 patients showed focal spikes with dysrhythmia. The focus of the spike discharge on interictal EEGs migrated as shown in Table l. Details on a dipole tracing method analysis of EEG spike focus will be reported elswhere.* Genetic findings: High-resolution chromosome studies of the maternal grandfather, mother and 3 siblings showed a normal karyotype. Using 5 DNA markers localized at 15qll-q12, we showed a microdeletion of only D15S105 and also a submicroscopic deletion encompassing the GABA receptor /?,subunit gene in the maternal grandfather, mother and 3 siblings.'