MON-110 Utilization of GluCEST, a Novel Neuroimaging Technique, to Characterize the Brain Phenotype in Hyperinsulinism/Hyperammonemia Syndrome

BACKGROUND: Hyperinsulinism/Hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism. It is caused by gain-of-function mutations in glutamate dehydrogenase (GDH), a mitochondrial enzyme expressed in pancreatic β-cells, liver, kidney, and brain, and is responsible for metabolizing glutamate into α-ketoglutarate and ammonia. In addition to hyperinsulinemic hypoglycemia due to abnormal GDH activity in pancreatic β-cells, ~80% of patients have developmental delays, learning, or behavioral disorders and >60% have atypical absence seizures (Bahi-Buisson, 2008). These neurologic symptoms are not fully explained by hypoglycemia and are hypothesized to result from central nervous system (CNS) glutamate imbalance due to CNS GDH overactivity. Newer magnetic resonance imaging (MRI) techniques have allowed for sensitive estimation of CNS glutamate using Glutamate Chemical Exchange Saturation Transfer (GluCEST). We aimed to comprehensively characterize the biochemical and clinical neurologic phenotype of HI/HA leveraging GluCEST MRI. Methods: Subjects with confirmed HI/HA diagnosis and without contraindication to MRI had electroencephalogram (EEG), serum ammonia, and the following validated neurodevelopmental assessments: ABAS-3, BRIEF, and ASEBA CBCL (if <18 years) or ASR (if >18 years) completed. GluCEST MRI axial hippocampal and midsagittal slices were acquired on a 7.0T Siemens scanner and reported as GluCEST % contrast. Healthy control GluCEST % contrast data were obtained from a separate study using the same neuroimaging protocol. Results: 8 HI/HA subjects (4 female; mean age 28 years [range 16-56] years) participated to date. Median serum ammonia was 58 umol/L (IQR 39-89). 50% self-reported learning impairments and 37.5% self-reported prior ADHD diagnosis. Marked unilateral increase in hippocampal GluCEST % contrast was observed in 3/6 subjects (2 L>R; 1 R>L). Overall, median peak GluCEST % contrast level was significantly higher in HI/HA subjects than controls (10.3% [IQR 8.9-11.3] v. 8.0% [IQR 7.8-8.4], p=0.0013, n=6). Conclusions: This is the first study to evaluate CNS glutamate via GluCEST in HI/HA. Hippocampal glutamate, measured by GluCEST % contrast, was significantly higher in HI/HA subjects than healthy controls. Laterality in hippocampal glutamate was observed in half of subjects. These findings are remarkable given the known role of abnormal glutamate signaling in the development of epilepsy and neurocognitive impairment. Next steps are to complete midsagittal GluCEST image processing, EEG and neurodevelopmental assessment interpretations to explore correlations between CNS phenotype and brain glutamate pattern. GluCEST holds promise for elucidating the pathophysiology of CNS manifestations in HI/HA syndrome.