AMINOGLYCOSIDE ENHANCEMENT OF GLUCOSE TRANSPORT IN GLUT1 DEFICIENCY SYNDROME

Objectives: To ameliorate GLUT1 deficiency by pharmacologically decreasing translational fidelity in a series of patient cellular cultures haploinsufficient for Glut1. It has been known for over 20 years that premature termination codons can be 'read through' in the presence of certain aminoglycosides, and certain derivatives are now being proposed for use in selected human diseases.

Methods: Radiolabeled glucose uptake measurements were performed in fibroblasts harvested from six patients carrying nonsense mutations leading to a premature termination codon in one Glut1 allele. Cells were exposed to the aminoglycosides gentamycin and G418 and Glut1 gene function assayed.

Results: Patients exhibited the classic GLUT1 deficient phenotype with decreased CSF glucose, epilepsy, pyramidal tract dysfunction, and neurobehavioral abnormalities. Patient fibroblast glucose uptake was significantly reduced compared to control to a degree that suggested the presence of a minimally functioning mutant allele. Exposure to gentamycin resulted in increased glucose uptake in a subset of patients and G418 identified an additional overlapping subset of responsive patients.

Conclusion: GLUT1 loss of function arising from de novo stop codon mutations leading to prematurely truncated Glut1 transporters can be partially corrected in patient fibroblasts. While only a minority of patients diagnosed to date carry this particular type of mutation, our results support the applicability of decreased translational fidelity as a potential therapeutic approach in GLUT1 Deficiency Syndrome and related diseases. Colleen Giblin