(31) Serotonergic Medication Reduces Seizure Frequency in a Patient with Sunflower Syndrome and Novel UBE3A Gain of Function Variant

Background: UBE3A is an E3 ubiquitin ligase that is crucial for brain development. While loss-of-function variants are classically associated with Angelman syndrome, numerous gain-of-function variants have also been characterized with little known clinical significance. These gain-of-function mutations have most commonly been associated with neurodevelopmental disorders and seizures. Sunflower syndrome (SFS) is a form of treatment-resistant epilepsy disorder that has an unclear etiology with a poorly understood genetic component. No prior research has linked SFS to a UBE3A variant. SFS typically begins within the first decade of life and is characterized by highly stereotyped movements, including an attraction to light, eye fluttering, and hand-waving episodes, all of which are associated with its seizure semiology. A serotonergic medication, fenfluramine, has been found to have antiepileptic properties for severe refractory epilepsy, including for patients with SFS.

We present a 24-year-old female with a history of neurodevelopmental delay and severe intractable epilepsy with absence seizures since age five. Recently, she was found to have a novel UBE3A T787A gain-of-function variant and was diagnosed with SFS. Despite trialing multiple high-dose antiepileptic medications over the years, this patient experienced numerous episodes of breakthrough seizures. However, a significant reduction in her seizure frequency was observed following the initiation of a serotonergic medication that was given to treat mood symptoms.

Objectives: To evaluate a novel patient presentation with a UBE3A gain-of-function variant-related epilepsy and developmental delay who experienced a reduction in seizures after the initiation of serotonergic medications.

Design/Methods: N/A

Results: N/A

Conclusions: A deeper understanding of the genetic and biomedical underpinnings of SFS is essential for identifying the most effective treatments and facilitating the earlier recognition of this rare condition. Further efforts are needed to elucidate the genetic causes of this disorder and understand its connection to neurodevelopmental disorders. This case corroborates other work in this field, which proposes that serotonergic medications may help reduce seizure frequency. However, the mechanism by which these drugs work to reduce seizures is poorly understood. Further research is needed to understand how the UBE3A gain-of-function variants influence neurodevelopment and epilepsy through their complex interactions.