Clinical-Res-Project2

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PROJECT 2 - ABSTRACT Epilepsy has been considered an infrequent manifestation in UCD (1). However, we found the frequent occurrence of sub-clinical electrographic seizures ((ES); seizures detected on EEG without accompanying clinical manifestations) during acute hyperammonemic (HA) episodes in patients, especially neonates, enrolled in the UCDC longitudinal study (LS). This new finding raises the question of whether seizures play an important role in the pathophysiology of neurocognitive deficits in UCD patients and/or can represent a biomarker that correlates with brain damage in these disorders. In this project, we propose to systematically study the scope and role of ES in our LS UCD population, characterizing the onset, frequency, duration, localization (focal or generalized) EEG background features, and biochemical and clinical correlates, as well as any association of ES or EEG background with the subsequent development of epilepsy. We hypothesize that: 1) There is a correlation between significant increases in plasma ammonia and/or glutamine levels and the development of ES, and 2) ES play a role in the adverse neurocognitive outcome after HA encephalopathy, especially in the neonate with UCD. If ES are in fact associated with adverse neurocognitive outcome, whether as a cause or as an associated biomarker, this project will provide clinical trial readiness data to subsequently test the role of anti-epileptic drugs as neuroprotection agents during HA in UCD, and presents both an opportunity and critical need to develop new therapeutic strategies that are targeted to the brain. The UCDC multisite consortium represents an ideal venue to capture this information.