Intrathecal magnesium delivery for Mg plus plus -insensitive NMDA receptor activity due to GRIN1 mutation

• Type of Material: Article
• Authors: Sara A Lewis, Phoenix Childrens Hosp; Sheetal Shetty, Phoenix Childrens Hosp; Sean Gamble, Phoenix Childrens Hosp; Jennifer Heim, Phoenix Childrens Hosp; Ningning Zhao, University of Arizona; Gideon Stitt, Phoenix Childrens Hosp; Matthew Pankratz, Phoenix Childrens Hosp; Tara Mangum, Phoenix Childrens Hosp; Iris Marku, Phoenix Childrens Hosp; Robert B Rosenberg, Phoenix Childrens Hosp; Angus A Wilfong, Phoenix Childrens Hosp; Michael C Fahey, Monash University; Sukhan Kim, Emory University; Scott J Myers, Emory University; Brian Appavu, Phoenix Childrens Hosp; Michael C Kruer, Phoenix Childrens Hosp
• Language: English
• Date: 2023-08-03
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13023-023-02756-9
• Title of Journal or Parent Work: ORPHANET JOURNAL OF RARE DISEASES
• Volume: 18
• Issue: 1
• Start Page: 225
• End Page: 225
• Grant/Funding Information: Portions of this work were supported by NIH 1R01 grant NS106298 to MCK.
• Keywords: NMDA receptor; Genetics & Heredity; Life Sciences & Biomedicine; Terms epileptic encephalopathy; SULFATE; Research & Experimental Medicine; Medicine, Research & Experimental; ENCEPHALOPATHY; Cerebral palsy; GRIN Disorders; Dystonia; Neurodevelopmental Disorders; N-of-1 treatment trial; Science & Technology; Precision Medicine
• Research Categories: Health Sciences, Public Health; Biology, Cell; Biology, Genetics; Biology, Molecular; Health Sciences, Pharmacy; Health Sciences, Nutrition; Biology, Neuroscience

Abstract

Background: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. Results: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. Conclusion: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.