Epilepsy in Angelman syndrome: A scoping review

Abstract

Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence. More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).

Case Report: An Atypical Angelman Syndrome Case With Obesity and Fulfilled Autism Spectrum Disorder Identified by Microarray

“…Many aspects of the case presented here are consistent with previous reports of AS patients with the underlying cause of paternal UPD ( Lossie et al, 2001 ; Poyatos et al, 2002 ; Thompson and Bolton, 2003 ; Tsai et al, 2004 ; Varela et al, 2004 ; Saitoh et al, 2005 ; Bonati et al, 2007 ; Depienne et al, 2009 ; Horváth et al, 2013 ; Luk and Lo, 2016 ), who generally had a lower prevalence of seizure, normal head circumference and absence of hypopigmentation ( Lossie et al, 2001 ; Depienne et al, 2009 ; Horváth et al, 2013 ; Samanta, 2021 ). AS patients with UPD also have a higher risk of obesity than deletion type ( Lossie et al, 2001 ; Poyatos et al, 2002 ; Varela et al, 2004 ; Saitoh et al, 2005 ; Brennan et al, 2015 ; Luk and Lo, 2016 ).…”

Conceptualization and implementation of an interdisciplinary clinic for children with drug-resistant epilepsy during the COVID-19 pandemic

“…Other patients with multifocal or generalized epilepsy and children with epileptic encephalopathies benefited from genetic testing (a more defined pathway for genetic testing in the clinic can further improve the workflow), medical therapy, neuromodulation, dietary therapy, and palliative surgery. [16,[28][29][30][31]] Interestingly, we observed significantly more patients receiving a recommendation for VNS compared to dietary therapy. It is unclear if regular access of a neurosurgeon in the clinic caused a bias recommendation toward VNS.…”

Genotype–Phenotype Correlations in Angelman Syndrome

“…Seizure and microcephaly have been reported to be more common and severe in the deletion group [ 53 , 63 , 64 , 65 ]. The deletion subtype is associated with the most severe epilepsy phenotype; in contrast, non-deletion patients may have relatively late-onset seizures [ 64 , 66 ]. Mertz et al found that children with a deletion type had significantly reduced developmental age regarding visual perception, receptive language, and expressive language compared with those having a UBE3A mutation and pUPD [ 58 ].…”

“…Compared to the patients with deletion type, patients with paternal UPD have a much lower prevalence of epilepsy, better development and expressive language ability; some patients may even speak 2–7 words [ 58 , 59 ]. The UPD subtype is also associated with the lowest frequency of epilepsy and exhibits the least severe epilepsy phenotype [ 66 ]. Varela et al found that swallowing disorders, hypotonia, and microcephaly in the UPD type are less severe than those in the deletion type [ 57 ].…”