Glut1 Deficiency Summit Snapshots from Sandra

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Welcome to Science with Sandra and Happy July!

As you all know, the Glut1 Summit took place in Dallas from June 26th to the 29th. I don’t have words to express my gratitude to Glenna for all her hard work putting this conference together, for all the logistics and on-site work. Thanks to her, the board, the volunteers, speakers, sponsors, and attendees. Without you all, this magnificent event would not have been possible. I am recharged with gratitude to continue working hard for our community!

We are working on putting some resources together that will be available on our website, including presentations summaries, posters and slides shared by speakers. Meanwhile, I will give you a brief summary of each session of the Scientific portion.

The summit started with Day 1 of the scientific sessions. This day’s presentations were around the collaborative RM1 Team Science research grant that Dr. Juan Pascual and collaborators received from the NIH last year. We heard about all the projects involved in this grant around brain glucose metabolism in the context of GLUT1 Deficiency Syndrome. It was amazing to see how much the network of researchers studying GLUT1 Deficiency has grown and to learn how researchers from different fields including bioengineering, mathematics, neuroscience, biochemistry and molecular biology, are working together with one common goal: To have a better understanding of the disease and to develop better treatments.

On Day 2 we had four sessions. The first session was Electrophysiology. Some take aways from this session are that brain metabolism is perturbed during seizures and metabolites decrease during these events. The neurotransmitter GABA is the major inhibitory neurotransmitter and it’s major precursor is glucose, therefore, if glucose is reduced in GLUT1 Deficiency, this could possibly affect the production of GABA. We also learnt that glycolytic metabolism, or the oxidation of glucose by cells to generate energy, influences epigenetic factors, or chemical compounds that modify or mark the genome.

Regarding epilepsy in GLUT1 Deficiency, we learnt that loss of function mutations on the SLC2A1 gene seem to be involved in absence epilepsies in this condition. Loss of function mutations are mutations that lead to the reduction of the activity of a gene, by either preventing its production or by decreasing the activity of the protein produced by the gene. Absence epilepsies are linked with changes in brain circuitries. These type of epilepsies are common in patients with GLUT1 Deficiency; therefore is important to have a better understanding of them. Studies have revealed that inhibiting glycolysis in the thalamus, a region of the brain, can promote seizures. Since brain glucose levels are low in GLUT1 Deficiency patients, it is possible that glycolysis is reduced in the thalamus, therefore, promoting seizures.

Session 2 was around GLUT1 and the SLC2A1 gene. In addition to transporting glucose to cells, GLUT1 is also involved in the development of neural progenitor cells in the brain. GLUT1 expresses in the apical surface of radial glial cells, when these cells are actively dividing. Radial glial cells are cells specialized in the developing nervous system of all vertebrates. Studies showed that there are metabolic changes in early radial glial cells in the absence of GLUT1. In order to have a better understanding of the role GLUT1 plays in neural brain cell development, mini brains or brain organoids have been developed from patient derived induced pluripotent stem cells or iPSCs. The results show that brain organoids from GLUT1 Deficiency patients are smaller and show different morphology than the controls. In this session, we also learnt about the importance of determining variant pathogenicity and how the number of Variants of Unknown Significance (VUS) has significantly increased, and how this causes uncertainty for clinicians and families in relation to clinical management.

Finally, scientists have gained understanding on how GLUT1 is involved in the development of brain microvasculature, and that mice deficient in GLUT1 have less neurons in a specific area of the thalamus, displaying impaired learning and memory capabilities.

Session 3 was around Metabolism. Researchers explained how mice models of GLUT1 deficiency show decrease glycogen, or glucose storage molecules in the brain, in addition to lower levels of glycosylation, in particular fucosylation. Glycosylation is the process through which different molecules get sugar decorations that are necessary for their function. We had learnt that GLUT1 transports fucose, another type of sugar. This molecule is important in fucosylation. Studies using GLUT1 Deficient mice showed that mice treated with fucose have increased glucose uptake, increased levels of glycogen and improvement of their motor functions. 

We also learned how other conditions such as a neurodevelopmental disorder caused by monoallelic  HK1 variants share similarities with GLUT1 Deficiency, including low CSF glucose and low CSF/blood glucose ratio; however individuals with this disease have an increased CSF lactate. I think it would be important to consider this in cases where a variant on the SLC2A1 gene is not found but there is a low CSF glucose.

Session 4 was about Therapy development. In this session we heard about the possibility of a clinical trial for GLUT1 Deficiency, next year. Studies using GLUT1 Deficient mice showed that these mice have reduced GLUT1 expression, decreased astrocytic activity, decreased lactate and glycogen levels. Researchers showed that when treating GLUT1 Deficient mice with the candidate molecule that will be used in the future clinical trial, mice show increased glucose uptake, better motor function and improvement in motor coordination.

Regarding Gene therapy, scientists shared how they are developing an alternate approach that employs a regulatory molecule of the Glut1 gene (SLC2A1) that induces its expression instead of the using the SLC2A1 gene. In addition, new vectors that allow better targeting of brain endothelial cells for treatment in a more precise manner, have been created. These vectors are more specific targeting brain endothelial cells. Brain endothelial cells express GLUT1 and are the first point of contact for glucose coming into the Brain. 

There were talks about other possible molecules that could potentially be used to treat GLUT1 Deficiency. These molecules have been identified through high throughput screening studies and have shown positive effects on glucose uptake in in-vitro studies. Some of these molecules will be tested in endothelial cells developed from patient-derived iPSC cells and mice models of GLUT1 Deficiency.

The Scientific portion of the conference was a wonderful opportunity to learn from expert scientists in our community. The biggest highlight of this portion, were the collaborative efforts taking place in our research community, and how this conference opened even more avenues for collaborations across different disciplines. Thank you to all the speakers who presented at our Summit, and thank you to all the attendees, this Summit has been very successful and I’m hopeful for what is to come for our community around research and development of better treatments and eventually a cure for GLUT1 Deficiency.