Low glycemic index treatment for seizures in Angelman syndrome.

PURPOSE: The low glycemic index treatment (LGIT) is a high fat, limited carbohydrate diet used in the treatment of epilepsy. The purpose of this study was to assess the efficacy and tolerability of the LGIT for the treatment of refractory seizures in pediatric patients with Angelman syndrome. METHODS: A pediatric Angelman syndrome cohort with refractory epilepsy was treated with the LGIT and followed prospectively over 4 months. Parents recorded a daily seizure log for a minimum of 1 month prior to the start of treatment as well as throughout the LGIT trial. Electroencephalography (EEG) and neuropsychological assessments (Scales of Independent Behavior-Revised and the Vineland Adaptive Behavior Scales-2nd Edition were obtained for each subject at both baseline and 4-month follow-up time points. Clinical evaluations of subjects were completed by a neurologist and dietitian at the time of enrollment, as well as following both the first and fourth months of dietary therapy. At each time point, blood for laboratory chemistries was drawn and anthropometric measures were obtained. KEY FINDINGS: Six children (mean age 3.3 years, range 1.1-4.8) with genetically confirmed Angelman syndrome initiated the LGIT, and completed the trial with no significant adverse events. Cohort averages for indices of seizure severity were as follows: age of 1.6 years at seizure onset, 3 lifetime antiepileptic drugs tried (range 1-6), and baseline seizure frequency of 10.1 events/week (range: 0.4-30.9). All subjects had a decrease in seizure frequency on the LGIT, with five of six exhibiting >80% seizure frequency reduction. All posttrial EEG studies showed improvement and three of four children with epileptiform activity on his or her baseline EEG had no discharges present on follow-up EEG. Developmental gains were noted by parents in all cases, although few of these neurocognitive gains were statistically significant on neuropsychological assessment. SIGNIFICANCE: This is the first prospective study assessing the LGIT for epilepsy. Our results indicate that this dietary therapy is highly effective in treating Angelman syndrome-related seizures. The diet was well tolerated by subjects as evidenced by five of six subjects remaining on the LGIT after completion of the trial. Beyond the prospective trial window, all five subjects who remained on the diet had >90% seizure reduction after 1 year of LGIT therapy. Despite the small sample size in this prospective study, the results indicate a potentially higher degree of efficacy of the LGIT for the Angelman syndrome population than that observed in the general epilepsy population. Although this study is too small to make definitive recommendations, these results suggest that the LGIT is a promising treatment option for Angelman syndrome-related epilepsy.

Neurologic manifestations of Angelman syndrome.

Angelman syndrome is a neurogenetic disorder characterized by the loss or reduction of the ubiquitin-protein ligase E3A enzyme. Angelman syndrome results from a deletion or mutation of the maternally inherited 15q11.2-13.1 region, paternal uniparental disomy of chromosome 15, or an imprinting error. Epilepsy is common and may present with multiple seizure types, including nonconvulsive status epilepticus. Seizures are often intractable and typically require broad-spectrum antiepileptic medications. Dietary therapy has also proved successful in Angelman syndrome. Electroencephalographic patterns include notched δ and rhythmic θ activity and epileptiform discharges. Sleep disorders are also common, often characterized by abnormal sleep-wake cycles. Movement disorders are nearly universal in Angelman syndrome, most frequently presenting with ataxia and tremor. Neurocognitive impairment is always present to varying degrees, and expressive speech is typically severely affected. Individuals with Angelman syndrome often manifest psychiatric comorbidities including hyperactivity, anxiety, and challenging behaviors such as aggression and self-injury. We focus on a comprehensive whole-child approach to the diagnosis and long-term clinical care of individuals with Angelman syndrome.