Authors :
Presenting Author: Mongkol Chanvanichtrakool, MD – Children National Hospital
Andrea Gropman, American Board of Medical Genetics/Biochemical, American Board of Pediatrics/Neurodevelopmental Disease, American Board of Psychiatry & Neurology-Child Neurology – Neurogeneticist, Neurodevelopmental Pediatrics and Neurogenetics, Children National hospital; John Barber, Master of science, Biostatistics – Senior Staff Biostatistician, Biostatistics and Study Methodology, Children National hospital
Rationale:
Urea cycle disorders (UCD) are inherited inborn errors of metabolism caused by six enzymatic and two carrier defects, resulting in impaired clearance of waste nitrogen. The disease's severity and onset vary according to the remaining enzyme activity. Most patients present with metabolic decompensation with neurological symptom including seizures, lethargy, and/or brain edema. As a part of pathophysiology of seizure, the accumulation of glutamate, which is responsible for increased excitatory activity, and glutamine, an ammonia buffer produced by glutamate synthase, cause astrocyte swelling. There is limited data regarding seizure type and the association between ammonia level and seizure occurrence. In addition, there is no consensus guideline recommending EEG surveillance based on ammonia levels in UCD during a crisis. Therefore, this study will examine the relationship between ammonia and the occurrence of seizures in UCD patients with hyperammonemic crises.
Methods:
The clinical charts of the UCD-diagnosed patients at Children's National Hospital between 1990 and 2023 were reviewed. This data was collected as part of an IRB approved urea cycle rare disorders longitudinal study (LS) database. Data collection includes clinical characteristics, seizure types, EEG, and biochemical profiles.
Results:
We report that 58 of the 85 UCD patients enrolled in the LS at our site, had 163 hyperammonemic crises (1–13 per patient). Additionally, 21 patients (36%) with crises experienced seizures that occurred frequently with early onset disease. EEG monitoring during crises: EEG detected subclinical seizures in 8 of 15 (53%) crises of patients with clinical seizures, while subclinical seizure were detected in 3 of 11 (27%) crises of encephalopathy-only patients with high ammonia levels. Patients with higher ammonia have 2.65 (95%CI, 1.51-4.66) greater odds of seizure per every 100 mcmol/l increase in ammonia and those with higher glutamine have 1.14 (95%CI, 1.05-1.25) greater odds of seizure per every 100 mcmol/l increases in glutamine.
Conclusions:
During hyperammonemic events, there is a significant association between the levels of ammonia and the occurrence of seizures. The measurement of ammonia and glutamine can help physicians in predicting seizures. This study also highlights the importance of EEG monitoring during crises for patients who are having seizures or encephalopathy with high-level ammonia to identify subclinical seizures and provide appropriate treatment to prevent neuronal damage.
Funding:
This study is supported by National Center for Advancing Translational Sciences (NCATS) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (5U54HD061221;Gropman, PI)