Epilepsy in patients with Angelman syndrome

Abstract

Angelman syndrome (AS) is a neuro-behavioural, genetically determined condition, characterized by ataxic jerky movements, happy sociable disposition and unprovoked bouts of laughter in association with seizures, learning disabilities and language impairment. Most of the cases are hardly diagnosed during infancy as jerky movements, the cardinal sign, appear later in childhood.AS is caused by a variety of genetic mechanisms involving the 15q 11-13 chromosome. About 70% of cases are due to a "de novo" interstitial deletion in the long arm region, arising on the maternally inherited chromosome. The diagnosis is confirmed by methylation test or by mutation analysis of UBE3A gene. The deletion phenotype is generally linked to a more severe clinical picture in that 95% of patients manifest more severe seizures, severe mental and motor retardation, dysmorphic features and microcephaly.The pathogenesis of epilepsy in AS is still not fully understood. The presence in the commonly deleted region of a cluster of genes coding for 3 subunits of the GABAa receptor complex has lead to the hypothesis that GABA neurotransmission is involved.Epilepsy, often severe and hard to control, is present in 85% of patients within the first three years of life, although less than 25% develop seizures during the first year. It was observed that febrile seizures often precede the diagnosis. Most frequent types are atypical absences, generalized tonic-clonic, atonic or myoclonic seizures, with multiple seizure types occurring in 50% of deleted patients. There is still some doubt about the association with West syndrome.The EEG abnormalities are not themselves pathognomonic of AS and both background activity and epileptic discharges vary even in the same patient with time. Nevertheless, the existence of some suggestive patterns should facilitate the early diagnosis allowing the correct genetic counselling for the family. Some drugs seems to act better than others, Valproate, ethosuximide and clonazepam giving the best results.

TheDYRK1Agene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy

“…Dysmorphic features were unspecific but underdeveloped ear lobes appeared frequently (figure 1D). The presence of an epileptic disease starting with febrile seizures and characterised by the presence of atonic and myoclonic seizures is classic in AS,23 but EEG analysis did not reveal a specific EEG pattern of AS (theta slow waves bursts in particular) in both of our patients. Some other important findings of AS, that is, facial manifestations, clinical courses of epilepsy, and behaviour with smiling, were also not observed in patients with DYRK1A abnormalities.…”

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

“…Clinically, epilepsy or seizure disorder is one of the most common (80 to 95%) and devastating features in AS, which starts before 3 years of age in most cases (Fiumara et al 2010; Thibert et al 2013). The seizure phenotype is reported to be more prominent in AS patients with a maternal deletion of chromosomal 15q11-q13 region, presumably due to the haploinsufficiency of a cluster of GABA receptors including GABRB3 in the distal end (Dan 2009; DeLorey et al 1998; Egawa et al 2008).…”

Applicability of genetic polymorphism analysis for the diagnosis of Angelman syndrome and the correlation between language difficulties and disease phenotype

“…Angelman syndrome (AS) is a neurodevelopmental disorder (Dagli et al, 2012), with clinical features including severe mental retardation, characteristic facial features (deep set eyes; pointed chin; wide, smiling mouth; and blonde hair/blue eyes, especially in patients with a microdeletion in the gene), a happy disposition, jerky movements, gait ataxia, and behavioral problems (Fiumara et al, 2010). Patients with AS also often exhibit seizures, microcephaly, and autistic features (Peters et al, 2004).…”