Abstracts

Angelman syndrome (AS) is associated with deletion of the maternal chromosome 15q11.2-15q13 in [gt]70% of cases. Uniparental disomy, mutations of the UBE3A gene or of an imprinting center, cause an additional 15% of cases. Refractory epilepsy is particularly common in deletion-associated cases. Multiple seizure types occur including atypical absences and prolonged non-convulsive status epilepticus (NCSE). Anticonvulsant drugs (AEDs), often in combination, are incompletely effective.
Each of the molecular mechanisms known to be associated with AS causes dysfunction of the UBE3A gene product, the E3 ubiquitin-ligase protein. In deletion cases other genes, including the gene encoding g-aminobutyric acid (GABA[sub]A[/sub]) [beta]3 subunit is deleted. A model for AS, mice lacking the [beta]3 subunit, show myoclonic jerks, abnormal EEG and seizures with motor and learning defects. The [beta]3 subunit deficit may result in abnormal thalamocortical functioning, favoring atypical absence seizures and NCSE.
The ketogenic diet (KD) is an effective treatment for refractory epilepsy. The mechanisms by which the KD exerts its anticonvulsant effect are not known. Proposed molecular targets include mitochondrial uncoupling proteins, potassium channels and, of interest for deletion-positive AS patients, GABA-ergic neurotransmission favoring inhibitory effect.
In this context we present 3 patients with Angelman syndrome and refractory epilepsy who were successfully treated with the ketogenic diet., A modified ketogenic diet (brief fast, full hydration, acid-base correction) was initiated in hospital after neurological, nutritional and neurometabolic testing revealed no contraindication to the KD. Final KD ratio was determined based on efficacy and level of ketosis., A: 3 year old girl, deletion positive AS and refractory NCSE, on 4 AEDs. Seizure free without complications on KD. Improved alertness, motor control, respiratory health, wellbeing.
B: 2 year old boy, deletion positive AS, on 2 AEDs. Seizure free off AEDs on KD. More alert, more progress.
C: 14 year old boy, one of 2 affected sibs with linkage to 15q11-13 but no mutation, with refractory status epilepticus, on 5 AEDs. Decrease in admissions for status epilepticus from 5/year to 1/3 years. Continued rarer seizures. Improved alertness, wellbeing. No adverse effects., Epilepsy in 2 deletion-positive AS cases was completely controlled, and a useful response occurred in an undeleted case. Based on these initial observations we recommend consideration of KD treatment early in the course of refractory epilepsy in AS individuals. Different molecular pathology may underlie the differential response seen in these cases. There are now 2 animal models of AS available with different molecular characteristics. Further clinical and in vivo studies of the KD in AS may clarify the role of the KD and offer insights into the pathophysiology of epilepsy in AS and into KD mechanisms.,