Glut1 Deficiency Syndrome: Novel Pathomechanisms, Current Concepts, and Challenges

Abstract

Glut1 Deficiency Syndrome (Glut1DS) has emerged as a treatable, but complex entity. Increasing data on pathogenic mechanisms, phenotype, genotype, and ketogenic dietary therapies (KDT) are available, as summarized in this review. Many challenges remain: novel symptoms emerge and vary with age. In Glut1DS, KDT in pregnancy and the clinical features in neonates and adults are poorly understood. KDT are ineffective in some patients for reasons yet unknown. Research reaches beyond the concept of brain energy depletion by impaired GLUT1-mediated glucose transfer across the blood-brain barrier. Novel concepts investigate alternative substrates, transport mechanisms, and metabolic interactions of different brain cell types. Future, yet currently unavailable prospects are neonatal screening for Glut1DS, reliable biomarkers, predictors for outcome, and alternative therapies, along with and beyond KDT.

Keywords: De Vivo disease; GLUT1; Glut1 Deficiency Syndrome; Glut1DS; SLC2A1; hypoglycorrhachia; ketogenic dietary therapies; treatable.

FIGURE 1

Conformational sideview model for GLUT1 in the membrane as proposed by Mueckler and Makepeace [10]. The 12 transmembrane helices are shown with a large intracellular loop connecting helices 6 and 7. The amino‐ and carboxy‐termini are located in the cytosol. Amino acid residues as discussed in the text are shown in single‐letter code.

FIGURE 2

(a, b) Three‐dimensional structure of human GLUT1 (PDB ID: 5EQI) in the membrane plane depicting the positions of LOF pathogenic genetic mutations triggering GLUT‐DS. The positions of intracellular helices (ICHs) and several natural mutations (N34S, S66F, G76D, G91D, R126H/L, E146K, L156R/N, R218H, K256V, T310I, or R333W) in ball‐and‐stick model are highlighted. The structure was analyzed in a PyMol computer modeling program (http://www.pymol.org/). For clarity, two side views (a and b) are shown to depict the positions of genetic mutations with regard to the membrane plane (highlighted in light green). (c) A hypothetical model of oligomerization of WT‐GLUT1 and aggregation of misfolded mutant GLUT1. In the healthy state, the cooperativity among GLUT1 subunits leads to tetramerization or oligomerization. In Glut1DS, destabilizing pathogenic mutations may elicit unfavorable conformation, misfolding, and aggregation. With permission from Raja and Kinne (2020).

FIGURE 3

Schematic diagram of glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) at the blood–brain barrier (BBB) and in brain cells (adapted from [96]). Glucose. GLUT1: Facilitated glucose diffusion via GLUT1 across the endothelial cells in the BBB. In brain, entry into astrocytes and oligodendrocytes. GLUT3: Glucose entry in neurons. Lactate. Glucose is converted into lactate via glycolysis in endothelial cells and astrocytes. MCT 1: Facilitated diffusion of lactate and ketones across endothelial cells in the BBB. MCT1/4: Release/entry of lactate and ketones in astrocytes and oligodendrocytes. MCT2: Lactate and ketone entry in neurons. Others. Amino acid transporters, lipid transporters, and further solute transporters (others) are also expressed in the BBB. Astrocyte neuron lactate shuttle provides lactate to neurons, derived from glycolysis in astrocytes (dotted line).