Glucose Transporter Type I Deficiency and Other Glucose Flux Disorders

The majority of patients with glucose transporter type I deficiency (G1D) are haploinsufficient in SLC2A1, the gene that encodes the glucose transporter isoforms present both in the endothelial cells of the blood-brain barrier and in astrocytes. G1D is expected, on biochemical principles, to result in decreased blood to brain and intracerebral glucose flux and, in mice, this is associated with diminished cerebral acetyl-coenzyme A contents. Thus, G1D probably stems from depletion (or perhaps from repletion) of energetic precursors centrally situated with respect to cerebral metabolism. Paradoxically, G1D is not associated with global neural hypoexcitability as a result of diminished glucose influx, but with focal hyperexcitability: Spike-wave epilepsy and paroxysmal dyskinesia constitute the best-defined G1D syndromes. Many patients also exhibit dystonia, ataxia and dysarthria, either in isolation or in conjunction with other nonmotor manifestations such as intellectual disability and microcephaly. A ketogenic diet has been effective in controlling seizures but has had little measurable effect on the associated cognitive impairment and behavioral disturbances. As the number of cases increases worldwide, it becomes more important to expand our understanding of the clinical phenotypes and to explore alternative treatment strategies designed to mitigate the impact of impaired brain glucose influx during early neurologic development.