Abstracts

Rationale: Synaptic Ras-GTPase-activating protein, or SYNGAP1, gene mutations have been associated with intellectual disability, autism, and epilepsy (Jeyabalan & Clement2). Few studies examined the clinical presentation, evolution of epilepsy, and outcome in pediatric patients with SYNGAP1 mutations. We report four patients with SYNGAP1 anomalies with similar presentations and outcomes. Methods: Four pediatric patients with SYNGAP1 mutations were identified in our practice via next generation sequencing panels. Each patient was assigned a letter for identification. Patient data was retrospectively reviewed and divided into fourteen categories: name, date of birth, current age, sex, genetic mutation, parental testing, developmental status, comorbidities, EEG and MRI findings, age of onset of epilepsy, seizure types, failed and current AEDs. Results: 50% were male and 50% were female. Age ranged from 7-15 years (mean 9.25 years). All patients had a de novo mutation in SYNGAP1; however, each of these patients had a different copy variant. Three patients had additional genetic VOUS anomalies (PRRT2, GLI2, FOXRED1, KMT2D), most of maternal inheritance. Phenotypic presentation of this cohort was as follows. Patient B and C both had onset of epilepsy at 18 months of age, while Patient D had onset of epilepsy at age 23 months while Patient A had onset at 4 years of age. EEG findings were abnormal in all patients with background slowing, generalized spike and slow waves, or multifocal spikes and slow waves. MRI was normal in Patient B and D; however Patient A’s MRI showed prominent CSF space along with a pineal cyst and Patient C’s MRI showed mild periventricular leukomalacia. Seventy-five percent of patients had atonic seizures. Other seizure types included atypical absence, myoclonic tonic, and generalized tonic-clonic. These patients failed between 1-2 anticonvulsants. The range of current anticonvulsant medications is 1-4. All patients had global developmental delays. Comorbid conditions were autism (Patient A and C), behavioral issues (Patient A and D), sleep problems (Patient A), mental retardation (Patient B), and ADHD (Patient D). Conclusions: In this patient cohort of young children with epilepsy related to SYNGAP1 mutations, all patients had global developmental delays, comorbid psychiatric and neurodevelopmental conditions, and epilepsy, commonly with atonic seizures. Seventy-five percent had medically refractory epilepsy with onset of epilepsy under two years of age. This cohort failed treatment with either levetiracetam, lamotrigine, clobazam, or clorazepate. However, 75% of these patients responded better to valproic acid monotherapy, or adjunctive clonazepam or ethosuximide. Interestingly, MRI findings were either noncontributory or unremarkable in all patients. Due to the similar presentations and current status of these four patients with SYNGAP1 mutations, early implementation of valproic acid with close seizure follow-up may be beneficial for long-term outcomes. 2 Jeyabalan, N., & Clement, J. P. (2016). SYNGAP1: Mind the Gap. Front. Cell. Neurosci, 15 February 2016 Funding: None.