Glucose Transporter Type I Deficiency (G1D) at 25 (1990-2015): Presumptions, Facts, and the Lives of Persons With This Rare Disease

Abstract

Background: As is often the case for rare diseases, the number of published reviews and case reports of glucose transporter type I deficiency (G1D) approaches or exceeds that of original research. This can indicate medical interest, but also scientific stagnation.

Methods: In assessing this state of affairs here, we focus not on what is peculiar or disparate about G1D, but on the assumptions that have reigned thus far undisputed, and critique them as a potential impediment to progress. To summarize the most common G1D phenotype, we trace the 25-year story of G1D in parallel with the natural history of one of two index patients, identified in 1990 by one of us (G.M.R.) and brought up to date by the other (J.M.P.) while later examining widely repeated but little-scrutinized statements. Among them are those that pertain to assumptions about brain fuels; energy failure; cerebrospinal glucose concentration; the purpose of ketogenic diet; the role of the defective blood-brain barrier; genotype-phenotype correlations; a bewildering array of phenotypes; ictogenesis, seizures, and the electroencephalograph; the use of mice to model the disorder; and what treatments may and may not be expected to accomplish.

Results: We reach the forgone conclusion that the proper study of mankind-and of one of its ailments (G1D) -is man itself (rather than mice, isolated cells, or extrapolated inferences) and propose a framework for rigorous investigation that we hope will lead to a better understanding and to better treatments for this and for rare disorders in general.

Conclusions: These considerations, together with experience drawn from other disorders, lead, as a logical consequence, to the nullification of the view that therapeutic development (i.e., trials) for rare diseases could or should be accelerated without the most vigorous scientific scrutiny: trial and error constitute an inseparable couple, such that, at the present time, hastening the former is bound to precipitate the latter.

Keywords: G1D; Glut1 deficiency; blood brain barrier; natural history; triheptanoin.

Conflict of interest statement

Competing interests: None

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Transaxial FDG-PET images of a G1D patient of 9 years of age harboring a missense mutation (A) and of a 8 year old G1D patient with no mutation in the coding region of SLC2A1 (B). (C) illustrates a 20-year old normal scan for comparison. The images in A and B are virtually indistinguishable, illustrating the fact that DNA-mutation negative patients are phenocopies (in this and all other respects) of patients genetically diagnosed.

Figure 1

Transaxial FDG-PET images of a G1D patient of 9 years of age harboring a missense mutation (A) and of a 8 year old G1D patient with no mutation in the coding region of SLC2A1 (B). (C) illustrates a 20-year old normal scan for comparison. The images in A and B are virtually indistinguishable, illustrating the fact that DNA-mutation negative patients are phenocopies (in this and all other respects) of patients genetically diagnosed.

Figure 1

Transaxial FDG-PET images of a G1D patient of 9 years of age harboring a missense mutation (A) and of a 8 year old G1D patient with no mutation in the coding region of SLC2A1 (B). (C) illustrates a 20-year old normal scan for comparison. The images in A and B are virtually indistinguishable, illustrating the fact that DNA-mutation negative patients are phenocopies (in this and all other respects) of patients genetically diagnosed.

Figure 2

Expression of phosphorylated GLUT1 in the capillaries of the mouse brain. A: Normal mice. B: G1D mice. G1D is associated with a paucity of immunofluorescence arising from decreased phosphorylated GLUT1 in the context of decreased total GLUT1 protein (not shown). Staining performed with reagents described in [123].

Figure 2

Expression of phosphorylated GLUT1 in the capillaries of the mouse brain. A: Normal mice. B: G1D mice. G1D is associated with a paucity of immunofluorescence arising from decreased phosphorylated GLUT1 in the context of decreased total GLUT1 protein (not shown). Staining performed with reagents described in [123].

Figure 3

Schematic of brain glucose flux and metabolism Figure 1. Brain energetic substrate fluxes and glucose transporters. Cells represented include astrocytes (blue), capillaries (red) and a synapse (green). Blood glucose reaches neurons or astrocyes [124], where it is converted to glycogen (not shown), or exported to neurons either intact via GLUT1 (□) and GLUT3 (■), or following conversion into lactate. Ketone bodies readily access the brain through monocarboxylate transporters (not represented). Transporter-independent fluxes (probably of limited magnitude [125, 126]) may also occur.

Figure 4

Thalamocortical synchronization in G1D. Left: Thalamocortical slice preparation with 64-channel multi electrode array (MEA) positioned over the sensory barrel cortex. Center: Normal mouse: Field potential recording from MEA array positioned as in the left showing the 16 electrode positions as designated by the white box outlined in left. Right: G1D mouse: note the ~3 Hz oscillation in all the electrodes indicative of thalamocortical hypersynchronization. Slices were bathed in drug-free, 2.5 mM glucose-containing perfusate [9].

Figure 5

Impact of G1D diagnosis. Left: number of emergency visits before the diagnosis of G1D. Right: Emergency department visits following the diagnosis and treatment of G1D. Data from the G1D patient registry (G1DRegistry.org, n= 82 patients).