Prevalence of Angelman syndrome amongst referrals with epilepsy and developmental delay

Over the last 10–20years thebodyof evidence for a link between epilepsy and a number of chromosome imbalances has been increasing [Schinzel and Niedrist, 2001; Singh et al., 2002; Kumada et al., 2005; Ville et al., 2006]. Associated imbalances are largely autosomal and include deletion of the maternal 15q11.2q12 region (resulting in Angelman syndrome (AS)), tetrasomy of 15pter-q13 due to supernumerary inv dup 15 chromosomes, deletion of 17p13.3 (resulting in Miller-Dieker syndrome) and deletion of 4p16.3 (resulting in Wolf–Hirschhorn syndrome). Epilepsy has also been associated with mutations of the UBE3A and LIS1 genes, leading to the Angelman and Miller-Dieker syndrome phenotypes, respectively. AS is a severe neurobehavioral disorder caused by defects in the maternally derived imprinted region on 15q11.1-q11.3. In most cases AS occurs due to one of the following mechanisms: (1) A large interstitial deletion of 15q11-q13 (encompassing the AS and Prader-Willi loci) of the maternally inherited homologue; (2) paternal uniparental disomy of chromosome 15; (3) an imprinting defect; (4) a mutation in UBE3A; or (5) an unidentified mechanism. Patients exhibit severe developmental delay, profound speech impairment, ataxia, jerky movements, disorders of balance, and a specific behavior comprising an easily excitable personality characterized by inappropriate laughter. In addition patients may display other characteristics including microcephaly, hypopigmentation, and epilepsy; these features having a higher incidence in patients with the classical 4 Mb deletion andUBE3Amutations [Saitoh et al., 1994; Smith et al., 1996;Monclaet al., 1999; Espayet al., 2005]. Epilepsy in individuals with AS typically presents from 6 to 18 months of age, with myoclonic and absence seizures being prevalent. The seizures have a characteristic EEG pathology characterized by rhythmic triphasic delta waves of high amplitude with a maximum in the frontal area [Boyd et al., 1988; Laan et al., 1997; Minassian et al., 1998]. If present, epilepsy is one of the earlier recognizable symptoms ofAS,with craniofacial andbehavioral characteristics becoming apparent with advancing age [Schinzel and Niedrist, 2001]. The incidenceof seizures in individualswithAShas been reported as ranging from 67% to 91% [Lossie et al., 2001; Schinzel and Niedrist, 2001; Singh et al., 2002]. This has been demonstrated to be dependent on the etiology of the syndrome, epilepsy being present in 100% of individuals with the classical 4 Mb deletion, but only in 49% of those with UPD, imprintingdisorders,UBE3Amutationor unknownetiology [Lossie et al., 2001]. Kyllerman [1995] publishedhis observations froma study of a Swedish population of 48,873 individuals: 63 had severe mental retardation and epilepsy, 4 (6%) of whom were clinically diagnosed with typical AS (although only 2 were confirmed by cytogenetic or molecular genetic techniques). In light of these findings, it seemed that it might be good practice to test all individuals with a referral that included epilepsy and mental retardation for deletions in the Prader-Willi/Angelman critical region. We therefore carried out a study of patients in the South Thames (East) Region of the United Kingdom over a 7.5 years period. All postnatal samples received by the Cytogenetics Department, where the referral included developmental delay and epilepsy/seizures, but no other indicators of AS, were tested for a deletion of the 15q11.1-q11.3 AS region by fluorescence in situ hybridization (FISH) analysis, using the