Abstract
OBJECTIVE: The Developmental and Epileptic Encephalopathies (DEE) are associated with serious and life-long neurological conditions and risk of early mortality. Here we describe the chronic treatment of a boy with PLCB1-related DEE with enteral myo-inositol supplementation as an add-on therapy to standard antiseizure medications that had been ineffective, and present novel findings in our lethal Slc5a3 knockout mouse model to substantiate our hypothesis for a novel role of myo-inositol in prenatal life. METHODS: Myo-inositol levels were measured in plasma, urine, and cerebrospinal fluid (CSF) using stable isotope dilution and selected ion monitoring gas chromatography/mass spectrometry. Brain function and structure was monitored with magnetic resonance spectroscopy, magnetic resonance imaging and electroencephalograms. Safety studies were performed according to FDA requirements. RESULTS: Treatment was well tolerated without any reported adverse events. There was an improvement in seizure burden and stabilization of brain atrophy that was most evident in the first and second years of life. Myo-inositol administration to the pregnant Slc5a3 carrier mice increased the myo-inositol content in CSF of the Slc5a3 knockout pups, which prevented their death. INTERPRETATION: High-dose enteral myo-inositol supplementation was safely used in a patient with epileptic encephalopathy due to PLCB1 deletion, increasing CSF levels and improving seizures and brain atrophy. The hypothesized mechanism involves restoring a fetal-like state with increased membrane potential, thereby reducing neuronal firing. Based on our experience, we encourage the exploration of high-dose myo-inositol in clinical trials involving infants with severe epileptic encephalopathy.